CN101384610B - 新型11β-羟基雄甾-4-烯-3-酮 - Google Patents
新型11β-羟基雄甾-4-烯-3-酮 Download PDFInfo
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- CN101384610B CN101384610B CN2007800036603A CN200780003660A CN101384610B CN 101384610 B CN101384610 B CN 101384610B CN 2007800036603 A CN2007800036603 A CN 2007800036603A CN 200780003660 A CN200780003660 A CN 200780003660A CN 101384610 B CN101384610 B CN 101384610B
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- diene
- nitrae
- isosorbide
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Abstract
式I的化合物11β-羟基雄甾-4-烯-3-酮及其生理学可接收的盐;其中R4表示选自(A)、(B)和(C)的部分,条件是当R4表示部分(C)时,Z是S:
Description
技术领域
背景技术
具有抗炎性质的皮质甾类(或糖皮质激素)被广泛用于治疗皮肤、气道、眼睛、胃肠道、关节、中枢神经系统(CNS)等的炎症状况或疾病以及几种自身免疫疾病。一些用糖皮质激素治疗为药方的炎症性皮肤疾病是湿疹、牛皮癣、变应性皮炎、瘙痒、超敏反应等。采用糖皮质激素的气道炎症或变应性状况包括鼻、咽喉或肺的疾病如鼻炎(包括花粉病)、鼻息肉、哮喘(包括变应原诱导的哮喘反应)、慢性阻塞性肺疾病、间质性肺疾病、纤维化等。糖皮质激素(Glucocrticoid)施用也用于炎症性肠疾病如溃疡性结肠炎和局限性肠炎(克罗恩病);和炎症性关节疾病如类风湿性关节炎,其是自身免疫病。然而,施用皮质甾类除期望的药理效应之外通常在远离靶标组织的部位处可引起不期望的副作用或不利的副作用,即所谓的全身效应。所遇到的一些不期望的全身效应包括广泛的免疫抑制、增加的骨转换、生长受损、皮肤变薄、糖尿病、肥胖症、水潴留(water retention)、黄体酮和雌激素相关的疾病。因此期望的是这样的糖皮质激素:当用于慢性治疗时,其在治疗剂量下在靶标组织处具有有效抗炎活性,而具有最小的全身活性或者优选地不具有全身活性。
传统的糖皮质激素描述在以下专利中: ·美国专利号4335121(’121专利;印度参考文献未得到)----(S)-氟甲基6α,9α-二氟-11β-羟基-16α-甲基-17α-丙酰氧基-3-氧雄甾-1,4-二烯-17β-硫代甲酸酯(氟替卡松)·美国专利号3007923(’923专利;印度参考文献未得到)----16α-甲基-9α-氟-1,4-孕甾二烯-11β,17α,21-三醇-3,20-二酮(地塞米松)·美国专利号3929768(’768专利;印度参考文献未得到)示例了(11β,16α)-16,17-[亚丁基双(氧基)]-11,21-二羟基孕甾-1,4-二烯-3,20-二酮(布德松)·美国专利号4472393(’393专利;印度参考文献未得到)示例了(11β,16α)-9,21-二氯-17-[(2-呋喃甲酰基)氧]-11-羟基-16-甲基孕甾-1,4-二烯-3,20-二酮(莫米松糠酸酯)
上述药物是已经在临床应用中的有效的糖皮质素。然而,在高的多次有效剂量时,这些药物具有引起全身副作用的可能。
PCT公布WO 99/01467描述了治疗活性甾族化合物类或其盐或溶剂化物,其具有与甾类核的环戊烷环相连的内酯基团(如下所示)。这些化合物已被描述为具有减小的全身活性潜能,原因在于内酯体系在血浆中的相对不稳定性。本发明的化合物不具有与环戊烷环相连的内酯基团。
我们的兴趣在于开发在炎症的具体部位发挥作用而具有微小副作用或者不具有显著副作用的化合物,这使得我们发现了在本发明中所述的新型、安全的11β-羟基雄甾-4-烯-3-酮化合物。这些化合物具有有用的抗炎活性,同时在多次有效剂量下具有微小的全身效应或不具有显著的全身效应。
发明内容
其中Z表示O或S;R1表示氢或甲基,其可以处于α或β-构型,或者表示亚甲基;R2和R3相同或不同,并且各自独立地表示氢、卤素或甲基基团;
R5表示选自(C1-C10)-烷基、(C3-C13)-环烷基、-O-(C1-C10)-烷基、芳基或杂环的基团,其中环或环体系是未取代的或者被一个或多个的卤素、-OH、(C1-C3)-烷基、-O-(C1-C3)-烷基、(C3-C13)-环烷基取代;其中烷基或环烷基可以任选含有一个或多个不饱和和/或可以具有一个或多个引入其中的杂原子,以及在各种情况中,任选具有一个或多个氢原子被卤素、-OH、(C1-C3)-烷基、-O-(C1-C3)-烷基、(C3-C13)-环烷基取代;和
R6表示选自(C1-C8)-烷基、(C3-C13)-环烷基、芳基和杂环基的基团,其中环或环体系是未取代的或者被一个或多个选自下述的取代基取代:(C1-C8)-烷基、(C3-C13)-环烷基、卤素、O-(C1-C8)-烷基、O-(C3-C13)-环烷基、OCO-(C1-C3)-烷基、S(O)0-2(C1-C8)-烷基、COO-(C1-C8)-烷基、-OCO-O-(C1-C3)-烷基、-OCO-CO-O-(C1-C3)-烷基、CONH2、CONH-(C1-C8)-烷基、CON-[(C1-C8)-烷基]2、-NHCO-(C1-C8)-烷基、N-(C1-C8)-烷基-CO-(C1-C8)-烷基、-NHCO-O-(C1-C8)-烷基、-N-(C1-C8)-烷基-CO-O-(C1-C8)-烷基、-NHCONH-(C1-C8)-烷基、-N-(C1-C8)-烷基-CONH-(C1-C8)-烷基、-NHCONH-SO2-(C1-C8)-烷基、-N-(C1-C8)-烷基-CONH-SO2-(C1-C8)-烷基、-NO2、-CN;其中所述烷基或环烷基可以任选含有一个或多个不饱和,和/或可以具有一个或多个引入其中的杂原子,以及在各种情况中,任选具有一个或多个氢原子被卤素、-OH、(C1-C3)-烷基、-O-(C1-C3)-烷基或(C3-C13)-环烷基取代;
条件是当R4表示部分(A)——其中R6表示任选地含有一个或多个引入其中的杂原子的(C3-C13)-环烷基——时,该杂原子不是氮;
P和Q独立地选自氢和C1至C3烷基;或者P和Q可以与它们所连接的碳原子一起结合而形成由部分(A-1)表示的(C3-C8)-环烷基: 其中m1是1以及n2是0、1、2、3、4或5,R6是如上所定义的芳基;或者P和R6可以连接在一起形成如通过部分(A-2)表示的环状体系: 其中m1是1以及n2是0、1、2、3或4,环G是如上所定义的芳基;X表示双键或三键;和 J、K和L独立地选自:氢、卤素、(C1-C10)-烷基、(C3-C13)-环烷基、-OH、-O-(C1-C10)-烷基、-O-(C3-C13)-环烷基、-OCO-(C1-C10)-烷基、-OCO-(C3-C13)-环烷基、-OCO-CO-O-(C1-C10)-烷基、-OCO-CO-O-(C3-C13)-环烷基、-OCO-O-(C1-C10)-烷基、-OCO-O-(C3-C13)-环烷基、-OCO-NH-(C1-C10)-烷基、-OCO-NH-(C3-C13)-环烷基、-OCO-N-[(C1-C10)-烷基]2、-OCO-N-[(C3-C13)-环烷基]2、-OCO-NHSO2-(C1-C10)-烷基、-OCO-NHSO2-(C3-C13)-环烷基、-NH2,-NH-(C1-C8)-烷基、-N-[(C1-C8)-烷基]2、-NO2 和-CN;
其中所述烷基或环烷基可以任选含有一个或多个不饱和,和/或可以具有一个或多个引入其中的杂原子,以及在各种情况中,任选具有一个或多个氢原子被下述基团取代:卤素、-OH、(C1-C3)-烷基、-O-(C1-C3)-烷基、-OCO-(C1-C3)-烷基、-COOH,-COO-(C1-C5)-烷基、-COO-(C1-C5)-卤代烷基、-NHCO-(C1-C8)-烷基、-ONO2、-NH-(C1-C8)-烷基、-N-[(C1-C8)-烷基]2、-NO2、-CN、(C3-C13)-环烷基、芳基或杂环基;或者J和K与它们所连接的碳原子一起结合起来表示(C3-C13)-环烷基或-CO-基团,以及L如上定义;或者当n1是0时,J、K和L不存在;R7表示选自氢、卤素、芳基和CO-芳基的基团,其中环或环体系是未取代的或者如上所述被取代;
优选地,式I-B的化合物11β-羟基雄甾-4-烯-3-酮及其生理学可接受的盐; 式I-B其中Z表示O或S;R1表示氢或甲基,其可以处于α或β-构型,或者表示亚甲基;R2和R3相同或不同,并且各自独立地表示氢、卤素或甲基基团;
R5表示选自(C1-C10)-烷基、(C3-C13)-环烷基、-O-(C1-C10)-烷基、芳基或杂环的基团,其中环或环体系是未取代的或者被一个或多个的卤素、-OH、(C1-C3)-烷基、-O-(C1-C3)-烷基、(C3-C13)-环烷基取代;其中所述烷基或环烷基可以任选含 有一个或多个不饱和,和/或可以具有一个或多个引入其中的杂原子,以及在各种情况中,任选具有一个或多个氢原子被卤素、-OH、(C1-C3)-烷基、-O-(C1-C3)-烷基、(C3-C13)-环烷基取代;和m1是1;m2是0或1;m3是0或1;n1是0、1或2;P和Q是氢;X表示双键或三键;和
J、K和L独立地选自:氢、卤素、(C1-C10)-烷基、(C3-C13)-环烷基、-OH,-O-(C1-C10)-烷基、-O-(C3-C13)-环烷基、-OCO-(C1-C10)-烷基、-OCO-(C3-C13)-环烷基、-OCO-CO-O-(C1-C10)-烷基、-OCO-CO-O-(C3-C13)-环烷基、-OCO-O-(C1-C10)-烷基、-OCO-O-(C3-C13)-环烷基、-OCO-NH-(C1-C10)-烷基、-OCO-NH-(C3-C13)-环烷基、-OCO-N-[(C1-C10)-烷基]2、-OCO-N-[(C3-C13)-环烷基]2、-OCO-NHSO2-(C1-C10)-烷基、-OCO-NHSO2-(C3-C13)-环烷基、-NH2、-NH-(C1-C8)-烷基、-N-[(C1-C8)-烷基]2、-NO2和-CN。
其中Z表示S;R1表示氢或甲基,其可以处于α或β-构型,或者表示亚甲基;R2和R3相同或不同,并且各自独立地表示氢、卤素或甲基基团;R5表示选自(C1-C10)-烷基、(C3-C13)-环烷基、-O-(C1-C10)-烷基、芳基或杂环的基团,其中环或环体系是未取代的或者被一个或多个的卤素、-OH、(C1-C3)-烷基、-O-(C1-C3)-烷基、(C3-C13)-环烷基取代;其中所述烷基或环烷基可以任选含有一个或多个不饱和,和/或可以具有一个或多个引入其中的杂原子,以及在各种情况中,任选具有一个或多个氢原子被卤素、-OH、(C1-C3)-烷基、-O-(C1-C3)-烷基、(C3-C13)-环烷基取代;和 m1是1;m2是0; m3是0; n1是0、1或2; P和Q是氢; X表示三键;和
J、K和L独立地选自:氢、卤素、(C1-C10)-烷基、(C3-C13)-环烷基、-OH、-O-(C1-C10)-烷基、-O-(C3-C13)-环烷基、-OCO-(C1-C10)-烷基、-OCO-(C3-C13)-环烷基、-OCO-CO-O-(C1-C10)-烷基、-OCO-CO-O-(C3-C13)-环烷基、-OCO-O-(C1-C10)-烷基、-OCO-O-(C3-C13)-环烷基、-OCO-NH-(C1-C10)-烷基、-OCO-NH-(C3-C13)-环烷基、-OCO-N-[(C1-C10)-烷基]2、-OCO-N-[(C3-C13)-环烷基]2、-OCO-NHSO2-(C1-C10)-烷基、-OCO-NHSO2-(C3-C13)-环烷基、-NH2、-NH-(C1-C8)-烷基、-N-[(C1-C8)-烷基]2、-NO2和-CN。
具体实施方式
本发明涉及式I的化合物——新型安全的11β-羟基雄甾-4-烯-3-酮——及其生理学可接受的盐。
式I的化合物可以是非对映异构体及其混合物的形式。如本文所用,任何立体异构形式包括非对映异构体及其混合物。
在下文中提及式I的化合物包括式I的化合物及其生理学可接受的盐。
关于在此以及贯穿说明书所用的通用术语所包括的各种基团,下面的定义和解释是适用的:
如本文所用,‘烷基’可以是直链或支化的并且可以任选含有一个或多个不饱和,和/或具有一个或多个引入其中的杂原子,诸如,举例来说,氮、氧或硫,并且在每一情况中,任选具有一个或多个氢原子被-F、-Cl、-Br、-I、-OH、-OCO-(C1-C3)-烷基、(C3-C13)-环烷基、芳基或杂环基取代。
如本文所用,‘包括一个或多个不饱和的烷基’应当被理解为是指‘烯基’和/或‘炔基’。示例性烷基基团包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、正戊基、3-戊基、2-辛基和类似基团。示例性烯基基团包括乙烯基、丙烯基、1-丁烯基、(Z)-2-丁烯基、(E)-3-甲基丁-2-烯基、(E)-2,4-戊二烯基、(Z)-3-庚烯基及类似基团。
示例性炔基基团包括乙炔基、丙炔基、1-丁炔基、2-丁炔基、4-甲基-2-戊炔基、2,4-己二炔基及类似基团。
如本文所用,‘环烷基’应当被理解为是指单环、双环、三环和多环环体系,如降冰片烷基(norbornyl)、金刚烷基(adamantly)及类似基团。如本文所用的术语‘环烷基’可以任选含有一个或多个不饱和,和/或可以具有一个或多个引入其中的杂原子,诸如,举例来说,氮、氧或硫,-F、-Cl、-Br、-I、-OH、-OCO-(C1-C3)-烷基、(C3-C13)-环烷基、芳基或杂环基。
如本文所用,‘卤素’或‘卤基团’是指氟、氯、溴或碘。
如本文所用,芳基应当被理解为是指诸如苯基、萘基、蒽基、菲基的环体系,优选地,芳基是苯基。
如本文所用,杂环(heterocyle)或杂环式环(heterocyclic ring)是指取代或未取代的3至15元环;并且应当被理解为是指这样的环体系,其除碳之外还含有杂原子,例如,如氮、氧或硫。该定义进一步包括杂环或杂环基与苯环稠合的环体系。杂环或杂环式环的实例是:
杂芳基,如
苯并咪唑基、
1-[(C1-C6)-烷基]苯并咪唑基、
咪唑基、
2-或3-噻吩基、
2-或3-呋喃基、
苯并噻唑基、
2-,3-或4-吡啶基、
嘧啶基、
4-,5-或6-哒嗪-2H-基-3-酮、
4-,5-或6-哒嗪-2-(C1-C8)-烷基-2H-基-3-酮、
2-苄基-4-,-5-或-6-哒嗪-2H-基-3-酮、
3-或4-哒嗪基、
2-,3-,4-或8-喹啉基、
1-,3-或4-异喹啉基、
1-二氮杂萘基、
3-或4-噌啉基、
2-或4-喹唑啉基、
2-吡嗪基、
2-喹喔啉基、
2-,4-或5-噻唑基、
3-,4-或5-异噻唑基、
1-[(C1-C6)-烷基]-2-,-4-或-5-咪唑基、 3-,4-或5-吡唑基、1-[(C1-C6)-烷基]-3-,-4-或-5-吡唑基、1-或4-[1,2,4]-三唑基、4-或5-[1,2,3]-三唑基、1-[(C1-C6)-烷基]-4-或-5-[1,2,3]三唑基、3-,4-或7-吲哚基、N-[(C1-C6)-烷基]-3-,-4-或-7-吲哚基、2-[(C1-C6)-烷基]-3(2H)-吲唑基、1-[(C1-C6)-烷基]-3(1H)-吲唑基、5-四唑基、1-[(C1-C6)-烷基]-1H-四唑基、2-[(C1-C6)-烷基]-2H-四唑基。
在一个实施方式中,优选的式I化合物选自其中m1是1的化合物。
在一个实施方式中,优选的式I化合物选自其中m1是1并且P和Q是氢的化合物。
在一个实施方式中,式I化合物选自其中R4表示部分(A)的化合物。
在一个实施方式中,式I化合物选自其中R4表示部分(B)的化合物。
在一个实施方式中,式I化合物选自其中R4表示部分(C)的化合物。
在一个实施方式中,式I化合物选自这样的化合物,其中m1是1;P和Q都是氢并且R4表示部分(A)。
在一个实施方式中,式I化合物选自这样的化合物,其中m1是1;P和Q都是氢并且R4表示部分(B)。
在一个实施方式中,式I化合物选自这样的化合物,其中m1是1;P和Q都是氢并且R4表示部分(C)。
在一个实施方式中,式I化合物选自这样的化合物,其中R6选自(C1-C8)-烷基、芳基和杂环基,其中环或环体系是未取代的或取代的,如上所定义。
在一个实施方式中,式I化合物选自这样的化合物,其中R5表示选自R6 的基团,其中R6选自(C1-C8)-烷基和杂环基,其中环或环体系是未取代的或取代的,如上所定义。
R1表示氢或甲基,其可以处于α或β-构型,或者表示亚甲基;R2和R3相同或不同,并且各自独立地表示氢、卤素或甲基基团;m1是1、2或3;
R6表示选自(C1-C8)-烷基、(C3-C13)-环烷基、芳基和杂环基的基团,其中环或环体系是未取代的,或者被一个或多个取代基取代,所述取代基选自:(C1-C8)-烷基、(C3-C13)-环烷基、卤素、O-(C1-C8)-烷基、O-(C3-C13)-环基、OCO-(C1-C3)-烷基、S(O)0-2(C1-C8)-烷基、COO-(C1-C8)-烷基、-OCO-O-(C1-C3)烷基、-OCO-CO-O-(C1-C3)-烷基、CONH2、CONH-(C1-C8)-烷基、CON-[(C1-C8)-烷基]2、-NHCO-(C1-C8)-烷基、N-(C1-C8)-烷基-CO-(C1-C8)-烷基、-NHCO-O-(C1-C8)-烷基、-N-(C1-C8)-烷基-CO-O-(C1-C8)-烷基、-NHCONH-(C1-C8)-烷基、-N-(C1-C8)-烷基-CONH-(C1-C8)-烷基、-NHCONH-SO2-(C1-C8)-烷基、-N-(C1-C8)-烷基-CONH-SO2-(C1-C8)-烷基、-NO2、-CN;
其中所述烷基或环烷基可以任选含有一个或多个不饱和,和/或可以具有一个或多个引入其中的杂原子,以及在各种情况中,任选具有一个或多个氢原子被-F、-Cl、-Br、-I、-OH、-OCO-(C1-C3)-烷基、(C3-C13)-环烷基、芳基或杂环基取代;条件是当R4表示部分(A)——其中R6表示任选地含有一个或多个引入其中的杂原子的(C3-C13)-环烷基——时,该杂原子不是氮;
P和Q独立地选自氢、卤素和C1至C3烷基;或者P和Q可以与它们所连接的碳原子一起结合而形成由部分(A-1)表示的(C3-C8)-环烷基: 其中m1是1以及n2是0、1、2、3、4或5;或者P和R6可以连接在一起形成如通过部分(A-2)表示的环状体系:
其中m1是1以及n2是0、1、2、3或4,并且环G任选存在,其中G表示(C3-C8)-环烷基、芳基或杂环基,如上定义;R5表示选自R6、-O-R6或-N(R8)R6的基团,其中R6如上定义,并且R8表示氢、(C1-C6)-烷基或(C3-C6)-环烷基;
在一个实施方式中,式I-A的化合物选自这样的化合物,其中m1是1;P和Q都是氢;R6选自(C1-C8)-烷基、芳基和杂环基;或其中m1是1;P和Q都是氢;R6是芳基,其中环或环体系是未取代或如上所定义被取代的;或其中R6是苯基,其中环或环体系是未取代的或如上所定义被取代的。
R1表示氢或甲基,其可以处于α或β-构型,或者表示亚甲基;R2和R3相同或不同,并且各自独立地表示氢、卤素或甲基基团;m1是1、2或3;m2是0或1;m3是0或1;n1是0、1或2;P和Q独立地选自氢、卤素和C1至C3烷基;X表示双键或三键,和J、K和L独立地选自氢、卤素、(C1-C10)-烷基、(C3-C13)-环烷基、-OH,-O-(C1-C10)-烷基、-O-(C3-C13)-环烷基、-OCO-(C1-C10)-烷基、-OCO-(C3-C13)-环烷基、-OCO-CO-O-(C1-C10)-烷基、-OCO-CO-O-(C3-C13)-环烷基、-OCO-O-(C1-C10)-烷基、-OCO-O-(C3-C13)-环烷基、-OCO-NH-(C1-C10)-烷基、-OCO-NH-(C3-C13)-环烷基、-OCO-N-[(C1-C10)-烷基]2、-OCO-N-[(C3-C13)-环烷基]2、-OCO-NHSO2-(C1-C10)-烷基、-OCO-NHSO2-(C3-C13)-环烷基、-CO-[(C3-C10)N-环]、-OCO-[(C3-C10)N-环]、-NH2、-NH-(C1-C8)-烷基、-N-[(C1-C8)-烷基]2、-NO2、-CN、芳基和如上定义的杂环基,
或者J和K可以与它们所连接的碳原子一起结合起来表示(C3-C13)-环烷基或-CO-基团,并且L如上定义;R5表示选自R6、-O-R6或-N(R8)R6的基团,其中R6如上定义,并且R8表示氢、(C1-C6)-烷基或(C3-C6)-环烷基;
在一个实施方式中,式I-B的化合物选自这样的化合物,其中m1是1;P和Q都是氢;X表示双键或三键;m2是0;m3是0;n1是1,并且J、K和L独立地选自氢、卤素、-OH、-OCO-(C1-C10)-烷基和-OCO-O-(C1-C10)-烷基。
R1表示氢或甲基,其可以处于α或β-构型,或者表示亚甲基;R2和R3相同或不同,并且各自独立地表示氢、卤素或甲基基团;
R5表示选自(C1-C10)-烷基、(C3-C13)-环烷基、-O-(C1-C10)-烷基、芳基或杂环的基团,其中环或环体系是未取代的或者被一个或多个的卤素、-OH、(C1-C3)-烷基、-O-(C1-C3)-烷基、(C3-C13)-环烷基取代;其中所述烷基或环烷基可以任选含有一个或多个不饱和,和/或可以具有一个或多个引入其中的杂原子,以及在各种情况中,任选具有一个或多个氢原子被卤素、-OH、(C1-C3)-烷基、-O-(C1-C3)-烷基、(C3-C13)-环烷基取代;和m1是1;m2是0或1;m3是0或1;n1是0、1或2;P和Q是氢;X表示双键或三键;和J、K和L独立地选自:氢、卤素、(C1-C10)-烷基、(C3-C13)-环烷基、-OH、-O-(C1-C10)-烷基、-O-(C3-C13)-环烷基、-OCO-(C1-C10)-烷基、-OCO-(C3-C13)-环烷基、-OCO-CO-O-(C1-C10)-烷基、-OCO-CO-O-(C3-C13)-环烷基、-OCO-O-(C1-C10)-烷基、-OCO-O-(C3-C13)-环烷基、-OCO-NH-(C1-C10)-烷基、-OCO-NH-(C3-C13)-环烷基、-OCO-N-[(C1-C10)-烷基]2、-OCO-N-[(C3-C13)-环烷基]2、-OCO-NHSO2-(C1-C10)-烷基、-OCO-NHSO2-(C3-C13)-环烷基、-NH2、-NH-(C1-C8)-烷基、N-[(C1-C8)-烷基]2、-NO2 和-CN。
其中Z表示S;R1表示氢或甲基,其可以处于α或β-构型,或者表示亚甲基;R2和R3相同或不同,并且各自独立地表示氢、卤素或甲基基团;R5表示选自(C1-C10)-烷基、(C3-C13)-环烷基、-O-(C1-C10)-烷基、芳基或杂环的基团,其中环或环体系是未取代的或者被一个或多个的卤素、-OH、(C1-C3)-烷基、-O-(C1-C3)-烷基、(C3-C13)-环烷基取代;其中所述烷基或环烷基可以任选含有一个或多个不饱和,和/或可以具有一个或多个引入其中的杂原子,以及在各种情况中,任选具有一个或多个氢原子被卤素、-OH、(C1-C3)-烷基、-O-(C1-C3)-烷基、(C3-C13)-环烷基取代;和m1是1;m2是0;m3是0;n1是0、1或2;P和Q是氢;X表示三键;和J、K和L独立地选自:氢、卤素、(C1-C10)-烷基、(C3-C13)-环烷基、-OH,-O-(C1-C10)-烷基、-O-(C3-C13)-环烷基、-OCO-(C1-C10)-烷基、-OCO-(C3-C13)-环烷基、-OCO-CO-O-(C1-C10)-烷基、-OCO-CO-O-(C3-C13)-环烷基、-OCO-O-(C1-C10)-烷基、-OCO-O-(C3-C13)-环烷基、-OCO-NH-(C1-C10)-烷基、-OCO-NH-(C3-C13)-环烷基、-OCO-N-[(C1-C10)-烷基]2、-OCO-N-[(C3-C13)-环烷基]2、-OCO-NHSO2-(C1-C10)-烷基、-OCO-NHSO2-(C3-C13)-环烷基、-NH2,-NH-(C1-C8)-烷基、-N-[(C1-C8)-烷基]2、-NO2 和-CN。
R1表示氢或甲基,其可以处于α或β-构型,或者表示亚甲基;R2和R3相同或不同,并且独立地表示氢、卤素或甲基基团;m1是1、2或3;
P和Q独立地选自氢、卤素和C1至C3烷基;R7表示选自卤素、CO-芳基和R6的基团,其中CO-芳基的芳环是未取代的或者被一个或多个如上关于环或环体系所定义的取代基取代;
R6表示选自(C1-C8)-烷基、(C3-C13)-环烷基、芳基和杂环基的基团,其中环或环体系是未取代的,或者被一个或多个选自下述的取代基取代:(C1-C8)-烷基、(C3-C13)-环烷基、卤素、O-(C1-C8)-烷基、O-(C3-C13)-环烷基、OCO-(C1-C3)-烷基、S(O)0-2(C1-C8)-烷基、COO-(C1-C8)-烷基、-OCO-O-(C1-C3)-烷基、-OCO-CO-O-(C1-C3)-烷基、CONH2、CONH-(C1-C8)-烷基、CON-[(C1-C8)-烷基]2、-NHCO-(C1-C8)-烷基、N-(C1-C8)-烷基-CO-(C1-C8)-烷基、-NHCO-O-(C1-C8)-烷基、-N-(C1-C8)-烷基-CO-O-(C1-C8)-烷基、-NHCONH-(C1-C8)-烷基、-N-(C1-C8)-烷基-CONH-(C1-C8)-烷基、-NHCONH-SO2-(C1-C8)-烷基、-N-(C1-C8)-烷基-CONH-SO2-(C1-C8)-烷基、-NO2、-CN;
其中所述烷基或环烷基可以任选含有一个或多个不饱和,和/或可以具有一个或多个引入其中的杂原子,以及在各种情况中,任选具有一个或多个氢原子被-F、-Cl、-Br、-I、-OH、-OCO-(C1-C3)-烷基、(C3-C13)-环烷基、芳基或杂环基取代;
R5表示选自R6、-O-R6或-N(R8)R6的基团,其中R6和R8如上定义。
在一个实施方式中,式I-C的化合物选自这样的化合物,其中m1是1;P和Q都是氢,并且R7表示R6,其中R6选自(C1-C8)-烷基或者其中环或环体系是未 取代的或者如上定义被取代的芳基。
生理学可接受的盐特别适合医学应用,原因在于它们相比起始化合物或基础化合物在水中具有更大的溶解度。本发明化合物的合适的生理学可接受的酸加成盐例如可以是无机酸如盐酸、氢溴酸、磷酸等的盐,或者可以是有机酸如乙酸、苯磺酸、苯甲酸、柠檬酸等的盐。合适的生理学可接受的碱式盐的实例是铵盐、碱金属盐如钠盐和钾盐,以及碱土金属盐如镁盐和钙盐。
式I的化合物在人药或兽药中有用,特别是用作抗炎药和抗过敏药。
式I的化合物具有潜在有益的抗炎或抗过敏效果,这通过例如其下列能力得到证实:其与糖皮质激素受体体外结合;并且抑制巴豆油诱导的耳水肿、棉球诱导的肉芽肿、葡聚糖凝胶诱导的肺水肿体内模型,而不引起如胸腺退化、肝中糖原沉积增强或者可感知的体重变化等全身副作用。
在本文中对式I化合物(一种或多种)的所有指代是指式(I)的化合物/多个化合物以及是指其盐。
本发明提供了制备式I化合物的方法,其包括使式II的化合物与式III的化合物R4-Y反应(方案-I): 方案-I 表示单键或双键,和 表示α或β-构型。其中Z表示O或S;R1、R2、R3、R4和R5如上定义;Y表示离去基团;
在式III的化合物中,Y表示合适的离去基团。合适的离去基团是在式II的化合物与式III的化合物反应时促进式I化合物形成的任何基团。例如,Y可以是卤素、烷基磺酸盐或芳基磺酸盐基团,如甲磺酸盐、对甲苯磺酸盐或三氟甲磺酸盐基团。
在一个实施方式中,本发明也提供了式I-A的化合物以及式I-A化合物的制备方法,其包括使式II-A的羧酸化合物(式II的化合物,其中Z是O)或式II-B的硫代羟酸化合物(式II的化合物,其中Z是S)与式III-A的化合物反应(方案-II): 方案-II 表示单键或双键,和 表示α或β-构型。其中Z表示O、S;R1、R2、R3、R5、R6、Y、P、Q和m1如上所述;
在合适的碱——例如碱金属或碱土金属碳酸盐,如碳酸钾、碳酸钠、碳酸氢钠等——存在下,由方案I或II表示的反应可以有利地在合适的惰性有机极性溶剂或溶剂系统中进行,例如丙酮、乙腈、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲亚砜及其类似物或其混合物。
式II的起始化合物在本领域是已知的,或者可以通过下面已知的方法制备,例如Gordon J.Phillips等,J.Med.Chem.,37,3717-3729(1994);美国专利号4335121;PCT公布号WO 04/001369或WO 04/039827,通过参考引入本文。
优选地,式II-A的化合物(式II的化合物,其中Z是O)可以如下制备:在有机碱如三乙胺或无机碱如碳酸钾存在下,用式R5COOH的化合物或其活性衍生物诸如其活化酯、酸酐或卤化物,特别是酰基卤例如酰基氯,处理式IV-A的化合物。为得到式II-A的化合物——其中R5表示-O-R6或-N(R8)R6,在有机碱如三乙胺或无机碱如碳酸钾存在下,使式IV-A的化合物与相应的R6-O-CO-Y′或R6(R8)N-CO-Y′——其中Y′表示诸如卤化物、4-硝基苯酚盐之类的离去基团——反应。为得到式II-A的化合物——其中R5表示-N(R8)R6并且R8是氢,可以使式IV-A的化合物与相应的异氰酸酯OCN-R6反应。式IV-A的化合物可以通过在化学氧化剂如高碘酸或高碘酸钠存在下氧化式V的化合物来制备。
优选地,式II-B的化合物(式II的化合物,其中Z是S)可以如下制备:式II-A的化合物首先与N,N-二甲基硫代氨甲酰氯反应,之后所产生的重排混合酸酐与二乙胺进行氨解,或者通过甲醇和碳酸钾进行甲醇分解,或者在合适的溶剂如N,N-二甲基甲酰胺中与氢硫化钠反应。
式II-B的化合物,其中Z是S,可以如下制备:在有机碱如三乙胺或无机碱如碳酸钾存在下,用式R5COOH的化合物或其活性衍生物诸如其活化酯、酸酐或卤化物,特别是酰基卤例如酰基氯,处理式IV-B的化合物。对于式II-B的化合物中——其中R5表示-O-R6或-N(R8)R6,在有机碱如三乙胺或无机碱如碳酸钾存在下,使式IV-B的化合物与相应的R6-O-CO-Y′或R6(R8)N-CO-Y′——其中Y′表示诸如卤化物、4-硝基苯酚盐之类的离去基团——反应。
式IV-B的化合物,其中Z是S,可以通过式IV-A的化合物与1,1′-羰基二咪唑进行羰基活化并且在合适的溶剂如N,N-二甲基甲酰胺中与硫化氢或氢硫化钠反应制备。
式II的化合物可以被方便地以其酸加成盐使用,优选为结晶形式。可以 使用任何合适的碱加成盐,例如钠盐或钾盐。
式III-A的化合物是已知的,或者可以通过本领域已知的方法制备。
在一个实施方式中,本发明提供式I-B的化合物及其制备方法,其包括使式II-A的羧酸化合物(式II的化合物,其中Z是O)或式II-B的硫代羟酸化合物(式II的化合物,其中Z是S)与式III-B的化合物反应(方案-IV): 方案-IV 表示单键或双键,和 表示α或β-构型。其中Z表示O或S;R1、R2、R3、R5、Y、P、Q、J、K、L、m1和n1如上定义,X表示双键或三键,m2是0或1以及m3是0或1;
式I-B的化合物可以通过式II的化合物与式III-B的化合物的烷基化来制备,该制备有利地在合适的碱——例如碱金属或碱土金属碳酸盐,如碳酸钾、碳酸钠、碳酸氢钠等——存在下,在惰性有机极性溶剂例如丙酮、乙腈、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲亚砜及其类似物中进行。式III-B的化合物是已知的或者可以通过本领域已知的方法来制备。
在一个优选的实施方式中,本发明提供式I-C化合物及其制备方法,该方法包括使式VI的化合物与式III-C的化合物反应(方案-V): 方案-V 表示单键或双键,和 表示α或β-构型。其中Z表示S;R1、R2、R3、R5、R7、Y、P、Q和m1如上定义;
式I-C的化合物可以通过式VI的化合物与式III-C的化合物的烷基化来制备,该制备在合适的碱——例如碱金属或碱土金属碳酸盐,如碳酸钾、碳酸钠、碳酸氢钠等——存在下,在惰性有机极性溶剂例如丙酮、乙腈、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲亚砜及类似物中有利地实施。式III-C的化合物是已知的或者可以通过本领域已知的方法来制备。
式VI的化合物可以如下制备:在极性有机溶剂如甲醇、乙醇、2-丙醇、乙酸等存在下,利用氧化剂——例如过氧化氢、脲-过氧化氢、过乙酸、间氯过苯甲酸、高碘酸钠等——氧化式II-B的化合物。
式I的化合物及其生理学可接受的盐还可以被用作制备其衍生物的中间体,例如-OH基团可以被转化为卤素基团或者可以被乙酰化或磺化,等等。
本发明也涉及用以局部施用的剂型,其取决于要被制备的制剂的精确类型,但是通常可以在按重量计0.001%至10%的范围内。然而,一般而言,对于大多数制剂类型,有利的是,所用的比例将在0.005%至1%、优选0.01%至0.5%的范围内。然而,以吸入或吹入用粉末,所用的比例可以在0.1%至5%的范围内。日剂量可以变化,其取决于被治疗的状况以及期望的治疗持续时间。
在一个实施方式中,用于获得期望生物效应的根据式I的化合物的量取决于很多因素,例如所选择的具体化合物、预期应用、给药类型以及患者的临床状态。一般而言,日剂量在0.01mg至500mg的范围内(典型从0.1mg至10mg)。口服施用的单剂量剂型如片剂或胶囊例如可以含有0.1mg至500mg,典型地从1mg至100mg。
在生理学可接受的盐的情况中,上述质量涉及加成盐所基于的游离化合物的质量。用于预防或治疗的化合物可以是根据式I本身的化合物,或者,在一个 实施方式中,它们以药物组合物连同合适的载体的形式存在。在一个实施方式中,就其与所述组合物的其它成分相容并且对患者健康无害的意义上来说,载体必须是天然可接受的。载体可以是固体或液体或者二者均可,并且优选与化合物作为单剂量配制,例如,作为片剂,该片剂可含有按重量计0.05%至95%的活性化合物。本发明的药物组合物可以根据任意已知的制药方法制备,该方法基本上包括混合成分与药学上可接受的载体和/或赋形剂。
本发明的另一方面涉及式I化合物以合适的形式配制以施用于对象。
本发明的药物组合物是适合口服、直肠、局部、经口(例如舌下)和肠胃外(例如皮下、皮内或关节内)施用的那些,尽管最合适的施用方式在每一个体情况下取决于被治疗的状况的性质和严重度以及取决于在每种情况下所用的式I化合物的性质。糖衣制剂和糖衣缓释制剂也包括在本发明的范围内。在一个实施方式中,优选耐酸肠溶制剂。合适的肠衣包括醋酸纤维素邻苯二甲酸酯、聚醋酸乙烯酯邻苯二甲酸酯(polyvinyl acetate phthalate)、羟丙基甲基纤维素邻苯二甲酸酯(hydroxypropylmethylcellulose phthalate)以及甲基丙烯酸和甲基丙烯酸甲酯的阴离子聚合物。
用于口服施用的合适的药物化合物可以以单独的单位存在,例如,作为胶囊、糯米纸包剂、锭剂或片剂,其在每种情况下含有特定量的根据式I的化合物;作为粉末或粒剂;作为在水性液体或非水液体中的溶液或悬浮液;或者作为水包油或油包水乳剂。这些组合物可以根据任何合适的制药方法制备,其包括使活性化合物与载体(其可以包括一种或多种另外的组分)接触的步骤。一般而言,通过均一和均匀地混合活性化合物与液体和/或充分分散的固体载体,之后如果必要的话,使产品成形,制备组合物。因此片剂例如可以通过压制或成型化合物的粉末或颗粒来制备,其适当地具有一种或多种其它组分。通过使化合物以自由流动的形式成片,可以制备压制的片剂,例如,粉末或颗粒在适当的情况下与粘合剂、润滑剂、惰性稀释剂和/或一种或多种表面活性/分散剂在合适的机器中混合。通过在合适的机器中成型用惰性液体稀释剂湿润的粉状化合物,能够制备成型的片剂。
适合经口(舌下)施用的药物组合物包括锭剂,其含有根据式I的化合物和通常为蔗糖和阿拉伯树胶或黄蓍胶的矫味剂,和含药锭,其包含在惰性基质中的化合物,所述惰性基质如明胶和甘油或者蔗糖和阿拉伯树胶。
用于肠胃外施用的合适的药物组合物例如可以包括根据式I的化合物的无菌制剂。这些制剂可以进行皮内施用,尽管它们也可以作为注射进行皮下、肌内或关节内施用。这些制剂可以通过混合化合物与水并使得到的溶液灭菌来制备。本发明的可注射组合物通常含有按重量计0.01%至5%的活性化合物。
用于直肠施用的合适的药物组合物作为单剂量栓剂存在。这些可以通过混合根据式I的化合物与一种或多种常规固体载体如可可脂并使所得混合物成型来制备。
用于外部施用于皮肤的合适的药物组合物可以作为软膏、乳膏、洗剂、糊剂、喷雾剂、气雾剂或油存在。可以使用的载体包括例如矿脂、羊毛脂、聚乙二醇、醇类以及两种或多种这些物质的组合。在一个实施方式中,活性化合物在范围在按组合物的重量计0.1%至15%的浓度下存在,例如按组合物的重量计0.5%至2%。
经皮施用也是可能的。用于经皮施用的合适的药物组合物可以作为单贴片存在,其适合长期紧密接触患者的表皮。此类贴片适当地含有在任选缓冲的水溶液中、溶解和/或分散在粘合剂或者分散在聚合物中的活性化合物。合适的活性化合物浓度是大约0.1%至35%,优选为大约1%至15%。特别可能的是通过电子输运或离子电泳作用的活性化合物释放,例如如在Pharmaceutical Research,2(6):318(1986)中所述。
在一个优选的实施方式中,式I的化合物适于局部施用。如本文所用的局部施用包括通过吹入和吸入的施用。用于局部施用的各种剂型包括软膏、洗剂、乳膏、凝胶、泡沫、通过贴片经皮输送的制剂、粉末、喷雾剂、气雾剂、用于吸入器或吹入器的药囊或药筒、或滴剂(例如,眼或鼻滴剂)、用于喷雾法的溶液/悬浮液、栓剂、阴道药栓、滞留灌肠剂(retention enemas)和可咀嚼片或可吸片或丸或微胶囊制剂。
软膏、乳膏和凝胶例如可以用水或油基质加入合适的增稠剂和/或胶凝剂和/或溶剂来配制。此类基质因此可以包括例如水和/或油如液体石蜡或植物油如花生油或蓖麻油(caster oil),或者溶剂如聚乙二醇。根据基质的性质可以使用的增稠剂和胶凝剂包括软石蜡、硬脂酸铝、十六醇十八醇混合物、聚乙二醇、羊毛脂、蜂蜡、羧基聚亚甲基(carboxypolymethylene)和纤维素衍生物,和/或单硬脂酸甘油酯和非离子乳化剂。
用于外部使用的粉末可以在合适的粉末基质的辅助下形成,例如滑石、乳糖或淀粉。滴剂可以用水或非水基质配制,该水或非水基质还包含药物、增溶剂、悬浮剂或防腐剂。
喷雾组合物例如可以作为水溶液或悬浮液或者作为加压包(pressurizedpack)如定剂量吸入器递送的气雾剂进行制备,其使用合适的液化推进剂。适于吸入的气雾剂组合物可以是悬浮液或溶液,并且通常含有式I的化合物和合适的推进剂如碳氟化合物或者含氢的氯氟烃或它们的混合物,特别是氢氟烷烃,尤其是1,1,1,2-四氟乙烷、1,1,1,2,3,3,3-七氟正丙烷或者它们的混合物。气雾剂组合物可以任选含有本领域熟知的其它配制赋形剂,如表面活性剂,例如油酸或卵磷脂以及助溶剂如乙醇。
有利地,本发明的制剂可以通过加入合适的缓冲剂进行缓冲。用在吸入器或吹入器中的药囊和药筒例如明胶可以被配制含有粉末混合物或者用于吸入本发明化合物的合适粉末基质如乳糖或淀粉。每一胶囊或药筒通常可以含有 20μg-1000μg之间的式I的化合物。可选地,本发明的化合物可以以无赋形剂如蔗糖的方式存在。
式I的活性化合物在根据本发明的局部组合物中的比例取决于被制备的制剂的精确类型,但是通常在按重量计0.001%至10%的范围内。然而,一般地,对于大多数类型的制剂,有利的是,所用的比例是从0.005%至1%,优选从0.01%至0.5%。然而,在用于吸入或吹入的粉末中,所用的比例将在0.1%至5%的范围内。
气雾剂制剂优选被安排,使得每个定剂量气雾剂或每“喷(puff)”气雾剂含有20μg-2000μg、优选大约20μg-500μg的式I的化合物。给药可以是每日一次或者每日数次,例如2、3、4或8次,例如每次给予1、2或3个剂量。气雾剂总的日剂量将在100μg-1000μg的范围内,优选地在200μg-2000μg的范围内。总的日剂量以及通过吸入器或吹入器中的囊和筒递送的定剂量通常将是气雾剂制剂的剂量的两倍。
局部制剂可以通过每日向受侵害区域施用一次或多次进行给药,可以有利地使用封闭覆裹法。通过粘胶贮库系统(adhesive reservoir system)可以实现连续的或延长的递送。
药物组合物可以是溶液或悬浮液,其包含治疗有效浓度的式I的化合物,具有或不具有治疗有效浓度的其它生物活性剂。组合物可以另外包含各种药学上可接受的赋形剂,如螯合剂、pH调节剂、缓冲剂、增粘剂、等渗剂、增溶剂、防腐剂、抗氧化剂等。
式I的化合物可以以药物递送系统如凝胶形成溶液的形式来制备。
对于内部施用,根据本发明的化合物例如可以以常规方式配制,用于口服、肠胃外或直肠施用。用于口服施用的制剂包括糖浆、酏剂、粉末、粒剂、片剂和胶囊,合适的话,其一般含有常规赋形剂,如粘合剂、填料、润滑剂、崩解剂、湿润剂、悬浮剂、乳化剂、防腐剂、缓冲盐、矫味剂、着色剂和/或增甜剂。然而,如下所述的剂量单位形式是优选的。
缓释或肠衣制剂可能是有利的,特别是对于炎症性肠疾病。
用于内部施用的优选制剂形式是剂量单位形式,即片剂和胶囊。此类剂量单位形式含有0.01mg至20mg本发明的化合物,优选为2.5mg至10mg。
本发明提供包含式I的化合物11β-羟基雄甾-4-烯-3-酮及其生理学可接受的盐的药物组合物。
本发明在一个实施方式中提供包含式I-A的化合物11β-羟基雄甾-4-烯-3-酮及其生理学可接受的盐的药物组合物。
本发明在一个实施方式中提供包含式I-B的化合物11β-羟基雄甾-4-烯-3-酮及其生理学可接受的盐的药物组合物。
本发明在一个实施方式中提供包含式I-C的化合物11β-羟基雄甾-4-烯-3- 酮及其生理学可接受的盐的药物组合物。
本发明被阐述,但是不限于在下面实施例中的描述。
实施例
实施例1
在0-5°,将高碘酸(4.59g,0.0201mol)的水(25ml)溶液(通过加热至50-55℃然后冷却至30-35℃制备)滴加到17α,21-二羟基-9,11-环氧-16α-甲基孕-1,4-二烯-3,20-二酮(5.0g,0.0134mol)于四氢呋喃(25ml)中的搅拌悬浮液中。在0-5℃将反应混合物搅拌2小时,在0-5℃将水加至该反应混合物中。过滤沉淀产物,用水洗涤,并干燥,产生为白色固体的标题化合物(4.75g,98.7%)。
1H NMR(400 MHz,在CDCl3中),δ:0.92(d,J=6.99Hz,3H),1.04(s,3H),1.29-1.36(m,1H),1.44(s,3H),1.41-1.82(m,4H),2.12-2.94(m,6H),3.19(s,1H),3.55-3.65(m,1H),6.11(s,1H),6.14(dd,J1=10.09Hz,J2=1.68Hz,1H),6.60(d,J=10.06Hz,1H)。
实施例2
在10-15℃,向9,11-环氧-17α-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-羧酸(4.5g,0.012mol)在丙酮(25ml)中的悬浮液中顺序加入三乙胺(5.3ml,0.038mol)和2-呋喃甲酰氯(4.96g,0.038mol)。在25-30℃搅拌4小时之后,在10-15℃滴加二乙胺(2.63ml,0.025mol),然后在环境温度下搅拌1小时。之后,在0-5℃将反应混合物酸化至pH1.0-1.5,过滤沉淀的产物,用水洗涤,并干燥,产生为白色固体的标题化合物(5.96g,99%)。
1H NMR(400 MHz,在CDCl3+DMSO-d6中),δ:0.98(d,J=7.09Hz,3H),1.07(s,3H),1.25-1.48(m,2H),1.46(s,3H),1.66-1.81(m,3H),2.02-2.74(m,6H),3.26(s,1H),3.26-3.32(m,1H),6.19(s,1H),6.22(dd,J1=10.13Hz,J2=1.76Hz,1H),6.53(dd,J1=3.44Hz,J2=1.61Hz,1H),6.64(d,J=10.04Hz,1H),7.15(d,J=3.37Hz,1H),7.62(d, J=0.81Hz,1H)。
实施例3
将9,11-环氧-17α-[(2-呋喃甲酰基)氧]16α-甲基-3-氧代雄甾-1,4-二烯-17β-羧酸(7.0g,0.0129mol)和N,N-二甲基硫代氨基甲酰氯(2.74g,0.0259mol)的四氢呋喃(35ml)溶液冷却至10至15℃并用三乙胺(2.86g,0.0283mol)和四丁基碘化铵(tetrabutulammonium iodide)(0.5g)处理。然后使反应混合物升至环境温度,搅拌4小时,然后加入N,N-二甲基乙酰胺(21ml)之后加入水(140ml)。将得到的混合物冷却至0℃,过滤产物,用水洗涤,并干燥,产生为浅黄色固体的标题化合物(6.6g,79.1%)。 1H NMR(400MHz,在CDCl3+DMSO-d6中),δ:1.01(d,J=7.11Hz,3H),1.15(s,3H),1.41-1.49(m,2H),1.46(s,3H),1.72-1.87(m,3H),2.19-2.73(m,6H),3.06(s,3H),3.16(s,3H),3.30(s,1H),3.30-3.32(m,1H),6.19(s,1H),6.22(dd,J1=10.02Hz,J2=1.74Hz,1H),6.58(dd,J1=3.51Hz,J2=1.68Hz,1H),6.64(d,J=10.09Hz,1H),7.22(d,J=3.51Hz),7.67(d,J=0.90Hz,1H)。
实施例4
将17β-[N,N-二甲基氨基甲酰基)硫代]羰基-9,11-环氧-17α-[(2-呋喃甲酰基)氧]-16α-甲基-3-氧代雄甾-1,4-二烯(5.0g,0.0106mol)和碳酸钾(2.94g,0.0213mol)在甲醇(25ml)中的悬浮液在氮保护下于环境温度下搅拌5小时。之后,向反应混合物中加入水并将得到的澄清溶液用甲苯洗涤。将含有产物的水层炭化,然后用2N HCl酸化,直到pH为1.5至2.0。过滤沉淀产物,用水洗涤,并干燥,产生为灰白色固体的标题化合物(3.6g,83%)。
1H NMR(400 MHz,在CDCl3中),δ:1.01(d,J=7.11Hz,3H),1.12(s,3H),1.36-1.48(m,2H),1.46(s,3H),1.72-1.81(m,3H),2.18-2.69(m,6H),3.28-3.31(m,1H), 3.31(s,1H),6.21(s,1H),6.25(dd,J1=10.08Hz,J2=1.76Hz,1H),6.55(dd,J1=3.48Hz,J2=1.61Hz,1H),6.63(d,J=10.06Hz,1H),7.23(dd,J1=3.45Hz,J2=0.58Hz,1H),7.64(d,J=0.97Hz,1H)。
实施例5
17β-[(N,N-二甲基氨基甲酰基)硫代]羰基-6α,9α-二氟-17α-[(2-呋喃甲酰基)氧]-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯
在10-15℃,向6α,9α-二氟-17α-[(2-呋喃甲酰基)氧]-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-羧酸(12.3g,0.025mol)和N,N-二甲基硫代氨基甲酰氯(9.29g,0.075mol)的四氢呋喃(60ml)溶液中加入三乙胺(10.48ml,0.075mol),并将四丁基碘化铵(0.92g)和混合物在环境温度下搅拌4小时。向反应混合物中加入二甲基乙酰胺(37ml)和水(310ml)并在0℃搅拌2小时。过滤所得到的固体,用水洗涤,并干燥,产生为白色固体的标题化合物(14.3g,99%)。
1H NMR(400 MHz,在CDCl3+DMSO-d6中),δ:1.00(d,J=7.10Hz,3H),1.19(s,3H),1.30-1.36(m,1H),1.54(s,3H),1.63-2.00(m,3H),2.22-2.60(m,4H),3.03(s,3H),3.16(s,3H),3.31-3.36(m,1H),4.29(d,J=8.91Hz,1H),5.39(br-s,1H),5.43-5.59(m,1H),6.22(s,1H),6.27(dd,J1=10.15Hz,J2=1.75Hz,1H),6.60(dd,J1=3.49Hz,J2=1.70Hz,1H),7.15(d,J=3.46Hz,1H),7.26(d,J=9.85Hz,1H),7.80(d,J=0.92Hz,1H)。
实施例6
在回流下将17β-[(N,N-二甲基氨基甲酰基)硫代]羰基-6α,9α-二氟-11β-羟基-16β-甲基-3-氧代-17α-丙酰氧基雄甾-1,4-二烯(5.0g,9.27mmol)在75ml二乙胺中的悬浮液加热8小时。将冷却的反应混合物倾倒入用2N HCl酸化至pH2的冰水中,并用乙酸乙酯萃取。将乙酸乙酯萃取物用水洗涤,干燥,并真空浓缩。将 得到的残余物从乙酸乙酯结晶,产生为浅黄色固体的标题化合物(3.2g,73.7%)。
1H NMR(400 MHz,在CDCl3中),δ:1.06(s,3H),1.16(t,J=7.52Hz,3H),1.20-1.25(m,1H),1.39(d,J=7.23Hz,3H),1.54(s,3H),1.67-2.05(m,4H),2.22-2.80(m,4H),2.39(q,J=7.69Hz,2H),4.45(br-d,J=7.69Hz,1H),5.30-5.50(m,1H),6.38(d,J=9.93Hz,1H),6.43(s,1H),7.15(dd,J=10.17Hz,1H)。
以类似的方法,制备6α,9α-二氟-17α-[(2-呋喃甲酰基)氧]-11β-羟基-16β-甲基-3-氧代雄甾-1,4-二烯-17β-硫代羟酸。
实施例7
将17β-[(N,N-二甲基氨基甲酰基)硫代]羰基-6α,9α-二氟-17α-[(2-呋喃甲酰基)氧]-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯(14.2g,0.024mol)和碳酸钾(6.78g,0.0491mol)在甲醇(70ml)中的悬浮液在氮保护下于环境温度下搅拌6小时。之后,向反应混合物中加入水并将得到的澄清溶液用甲苯洗涤。将含有产物的水层炭化,然后用2N HCl酸化,直到pH为1.5至2.0。过滤沉淀产物,用水洗涤,并干燥,产生为白色固体的标题化合物(11.8g,94.8%)。
1H NMR(400 MHz,在CDCl3+DMSO-d6中),δ:1.03(d,J=7.17Hz,3H),1.20(s,3H),1.31-1.37(m,1H),1.56(s,3H),1.73-2.03(m,3H),2.28-2.59(m,4H),3.37-3.42(m,1H),4.35-4.38(br-d,1H),4.89(d,J=1.22Hz,1H),5.34-5.51(m,1H),6.34(dd,J1=1 0.06Hz,J2=1.88Hz,1H),6.39(s,1H),6.53(dd,J1=3.45Hz,J2=1.73Hz,1H),7.14(dd,J1=3.28Hz,J2=0.49Hz,1H),7.25(dd,J1=10.12Hz,J2=1.30Hz,1H),7.63(dd,J1=1.73Hz,J2=0.63Hz,1H)。
下面的17β-硫代羟酸通过类似于实施例7的方法制备:
9α-氟-17α-[(2-呋喃甲酰基)氧]-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-硫代羟酸。
6α,9α-二氟-11β-羟基-16α-甲基-17α-[[(3-甲基-2-呋喃)羰基]氧基]-3-氧代雄甾-1,4-二烯-17β-硫代羟酸。
6α,9α-二氟-17α-[(3-呋喃甲酰基)氧]-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-硫代羟酸。
6α,9α-二氟-11β-羟基-16α-甲基-3-氧代-17α-[(2-噻吩甲酰基)氧]-雄■-1,4-二烯-17β-硫代羟酸。
17α-[[(5-氯-2-噻吩基)羰基]氧基]-6α,9α-二氟-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-硫代羟酸。
17α-环丙基羰氧基-6α,9α-二氟-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-硫代羟酸。
17α-环丁基羰氧基-6α,9α-二氟-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-硫代羟酸。
17α-环戊基羰氧基-6α,9α-二氟-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-硫代羟酸。
17α-环己基羰氧基-6α,9α-二氟-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-硫代羟酸。
17α-环己基甲基羰氧基-6α,9α-二氟-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-硫代羟酸。
9α-氟-11β-羟基-16α-甲基-3-氧代-17α-丙酰氧基雄甾-1,4-二烯-17β-硫代羟酸。
9α-氟-11β-羟基-16β-甲基-3-氧代-17α-丙酰氧基雄甾-1,4-二烯-17β-硫代羟酸。
6α,9α-二氟-11β-羟基-16α-甲基-3-氧代-17α-丙酰氧基雄甾-1,4-二烯-17β-硫代羟酸。
6α,9α-二氟-11β-羟基-16β-甲基-3-氧代-17α-丙酰氧基雄甾-1,4-二烯-17β-硫代羟酸。
17α-丁氧基(Butryloxy)-6α,9α-二氟-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-硫代羟酸。
6α,9α-二氟-11β-羟基-16α-甲基-3-氧代-17α-戊酰氧基雄甾-1,4-二烯-17β-硫代羟酸。
6α,9α-二氟-11β-羟基-16α-甲基-17α-(2-甲基丙酰)氧-3-氧代雄甾-1,4-二烯-17β-硫代羟酸。
17α-二氯乙酰氧基-6α,9α-二氟-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-硫代羟酸。
6α,9α-二氟-11β-羟基-17α-(甲氧基甲基羰基)氧-16α-甲基-3-氧代雄甾-1,4-二烯-17β-硫代羟酸。
6α,9α-二氟-17α-(乙氧基甲基羰基)氧-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-硫代羟酸。
17α-(乙氧基羰基)氧-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-硫代羟酸。
6α,9α-二氟-17α-(乙氧基羰基)氧-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-硫代羟酸。
实施例8-化合物IA.44
将2-溴-1-苯乙酮(0.438g,2.2mmol)和碘化钠(50mg)加入6α,9α-二氟-11β-羟基-16α-甲基-3-氧代-17α-丙酰氧基-雄甾-1,4-二烯-17β-羧酸(1.0g,2.20mmol)和无水碳酸钾(0.360g,2.6mmol)在丙酮(15ml)中的搅拌混合物中。在氮保护下在25至30℃将混合物搅拌8小时,然后倾倒入水中并用乙酸乙酯萃取。有机层用水洗涤两次,干燥,并在真空下浓缩。残余物通过柱层析(己烷中40%的乙酸乙酯)纯化,产生为白色固体的标题化合物。
使用式II的合适羧酸和式III-A的化合物,以类似于实施例8的方式制备下面的化合物:IA.1,IA.2,IA.4,IA.5,IA.7-IA.10,IA.12,IA.15-IA.19,IA.21,IA.23-25,IA.28-30,IA.32,IA.33,IA.36,IA.37,IA.42,IA.46,IA.48,IA50,IA.52,IA.54,IA.57,IA.60,IA.62-IA.67,IA.71,IA.72,IA.74,IA.76,IA.77,IA.80,IA.82,IA.84,IA.87,IA.91,IA.103,IA.115,IA.118,IA.121,IA.133。
实施例9-化合物IA.38
在氮保护下,在25至30℃,将2-溴-1-(4-三氟甲基苯基)乙-1-酮(0.569g,2.13mmol)、6α,9α-二氟-11β-羟基-16α-甲基-3-氧代-17α-丙酰氧基雄甾-1,4-二烯-17β-硫代羟酸(1.0g,2.13mmol)和无水碳酸钾(0.295g,2.13mmol)在丙酮(25ml)中的混合物搅拌3小时。然后将反应混合物倾倒入水中并用乙酸乙酯萃取。有机层用水洗涤,干燥,并在真空下浓缩。残余物通过柱层析(己烷中40%的乙酸乙酯)纯化,产生为白色固体的标题化合物。
使用式II的合适的硫代酸和式III-A的化合物,以类似于实施例9的方式制备下面的化合物: IA.3,IA.6,IA.11,IA.13,IA.14,IA.20,IA.22,IA.26,IA.27,IA.31,IA.34,IA.35,IA.39,IA.40,IA.43,IA.45,IA.47,IA.49,IA.51,IA.53,IA.55,IA.56,IA.58,IA.59,IA.61,IA.63,IA.68-IA.70,IA.73,IA.75,IA.78,IA.79,IA.81,IA.83,IA.85,IA.86,IA.88-IA.90,IA.92-IA.102,IA.104-IA.108,IA.110-IA.114,IA.116,IA.117,IA.119,IA.120,IA.122-IA.124,IA.126-IA.132,IA.134-IA.186,IA.198。
实施例10-化合物IA.59
将2-溴-2-甲基-1-苯基-丙-1-酮(0.483g,2.13mmol)加入6α,9α-二氟-11β-羟基-16α-甲基-3-氧代-17α-丙酰氧基雄甾-1,4-二烯-17β-硫代羟酸(1.0g,2.13mmol)和无水碳酸钾(0.295g,2.13mmol)在丙酮(20ml)中的搅拌混合物中,并且在氮保护下在25至30℃将混合物搅拌3小时。然后将反应混合物倾倒入水中并用乙酸乙酯萃取。有机层用水洗涤,干燥,并在真空下浓缩。残余物通过柱层析(己烷中40%的乙酸乙酯)纯化,产生为白色固体的标题化合物。
使用式II的合适的硫代酸和式III-A的化合物,以类似于实施例10的方式制备下面的化合物:IA.109,IA.187-IA.197。
实施例11-化合物IA-1.2
将(1-溴环戊基)苯甲酮(0.539g,2.13mmol)加入6α,9α-二氟-11β-羟基-16α-甲基-3-氧代-17α-丙酰氧基雄甾-1,4-二烯-17β-硫代羟酸(1.0g,2.13mmol)和无水碳酸钾(0.295g,2.13mmol)在丙酮(25ml)中的搅拌混合物中,并且在氮保护下在25至30℃将混合物搅拌3小时。然后将反应混合物倾倒入水中并用乙酸乙酯萃取。有机层用水洗涤,干燥,并在真空下浓缩。残余物通过柱层析(己烷中35%的乙酸乙 酯)纯化,产生为白色固体的标题化合物。
以类似于实施例11的方式制备化合物IA-1.1。
实施例l2-化合物IA-2.1
将2-溴-1-四氢萘酮(0.395g,1.75mmol)加入6α,9α-二氟-11β-羟基-16α-甲基-3-氧代-17α-丙酰氧基雄甾-1,4-二烯-17β-硫代羟酸(0.500g,1.06mmol)和无水碳酸钾(0.161g,1.17mmol)在丙酮(10ml)中的搅拌混合物中,并且在氮保护下在25至30℃将混合物搅拌3小时。然后将反应混合物倾倒入水中并用乙酸乙酯萃取。有机层用水洗涤,干燥,并在真空下浓缩。残余物通过柱层析(己烷中40%的乙酸乙酯)纯化,产生为白色固体的标题化合物。
实施例13-化合物IA.41
将2-溴-1-(2,4,6-三甲基苯基)乙酮(0.287g,1.13mmol)加入9,11-环氧-17α-[(2-呋喃甲酰基)氧]-16α-甲基-3-氧代雄甾-1,4-二烯-17β-硫代羟酸(0.600g,1.28mmol)和无水碳酸钾(0.194g,1.40mmol)在丙酮(25ml)中的搅拌混合物中,并且在氮保护下在25至30℃将混合物搅拌2.5小时。然后将反应混合物倾倒入水中并用乙酸乙酯萃取。有机层用水洗涤,干燥,并在真空下浓缩。将粗制固体溶解在冰醋酸(10ml)中并在10-15℃加入浓盐酸(1ml)。在15-20℃将混合物搅拌30min,倒入冰水(400ml)中,将产物过滤,用水洗涤,最后在热空气箱中干燥。将粗制固体通过柱层析(己烷中35%的乙酸乙酯)纯化,产生为白色固体的标题化合物。
实施例14-化合物IB.45
S-[4-羟基-丁-2-炔基]9α-氯-17α-[(2-呋喃甲酰基)氧]-11β-羟基-16α-甲基-3- 氧代雄甾-1,4-二烯-17β-硫代羟酸酯
将4-(四氢吡喃-2-氧基)-丁-2-炔基甲苯-4-磺酸酯(0.727g,2.24mmol)加入9,11-环氧-17α-[(2-呋喃甲酰基)氧]-17α-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-硫代羟酸(1.0g,2.13mmol)和无水碳酸钾(0.300g,2.34mmol)在丙酮(20ml)中的搅拌混合物中,并且在氮保护下在25至30℃将混合物搅拌4小时。然后将反应混合物倾倒入水中并用乙酸乙酯萃取。有机层用水洗涤,干燥,并在真空下浓缩。将粗制固体溶解在甲醇(15ml)中并在10-15℃加入浓盐酸(4ml)。在25-20℃将混合物搅拌30min,然后在60℃加热4小时。然后冷却混合物并倒入冰水中。将固体过滤,用水洗涤,并干燥。将粗制固体通过柱层析(在二氯甲烷中的3%甲醇)纯化,产生为白色固体的标题化合物。
实施例15-化合物IB.2
将4-氯-丁-2-炔-1-醇(0.169g,1.62mmol)加入6α,9α-二氟-11β-羟基-16α-甲基-3-氧代-17α-丙酰氧基雄甾-1,4-二烯-17β-硫代羟酸(0.800g,1.54mmol)和无水碳酸钾(0.234g,1.70mmol)在丙酮(20ml)的搅拌混合物中,并且在氮保护下在25至30℃将混合物搅拌3小时。然后将反应混合物倾倒入水中并用乙酸乙酯萃取。有机层用水洗涤,干燥,并在真空下浓缩。残余物通过柱层析(在二氯甲烷中的3%甲醇)纯化,产生为白色固体的标题化合物。
使用式II的合适的硫代酸和式III-B的化合物,以类似于实施例15的方式制备下面的化合物:IB.1,IB.4,IB.5,IB.7-IB.11,IB.20-IB.24,IB.26-IB.29,IB.38,IB.39,IB.61,IB.62,IB.132。
实施例16-化合物IB.25
S-[3-(1-羟基环己基)丙-2-炔基]6α,9α-二氟-17α-[(2-呋喃甲酰基)氧]-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-硫代羟酸酯
将4-甲基-[3-(羟基环己基)丙-2-炔基]苯磺酸盐(0.222g,0.72mmol)加入6α,9α-二氟-17α-[(2-呋喃甲酰基)氧]-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-硫代羟酸(0.350g,0.688mmol)和无水碳酸钾(0.104g,0.756mmol)在丙酮(20ml)中的搅拌混合物中,并且在氮保护下在25至30℃将混合物搅拌3小时。然后将反应混合物倾倒入水中并用乙酸乙酯萃取。有机层用水洗涤,干燥,并在真空下浓缩。残余物通过柱层析(己烷中35%的乙酸乙酯)纯化,产生为白色固体的标题化合物。以类似于实施例16的方式制备化合物IB.40。
实施例17-化合物IB.35
在10-15℃将戊酰氯(0.337g,2.79mmol)加入S-(4-羟基-丁-2-炔基)6α,9α-二氟-11β-羟基-16α-甲基-3-氧代-17α-丙酰-氧基雄甾-1,4-二烯-17β-硫代羟酸酯(0.5g,0.93mmol)和三乙胺(0.282g,2.79mmol)在丙酮(20ml)中的搅拌混合物中,并且在氮保护下在25至30℃将混合物搅拌8小时。然后将反应混合物倾倒入水中并用乙酸乙酯萃取。有机层用水洗涤,干燥,并在真空下浓缩。残余物通过柱层析(己烷中35%的乙酸乙酯)纯化,产生为白色固体的标题化合物。
以类似于实施例17的方式制备下面的化合物:IB.31-IB.37,IB.48-IB.53,IB.55-IB.60,IB.67-IB.73,IB.75-IB.86,IB.88,IB.92-IB.102,IB.104-IB.122,IB.124,IB.133,IB.135,IB.148,IB.155,IB.157。
实施例18-化合物IB.3
在25-30℃将三氟化二乙氨基硫(DAST)(0.151g,0.93mmol)加入S-(4-羟基-丁-2-炔基)6α,9α-二氟-11β-羟基-16α-甲基-3-氧代-17α-丙酰氧基雄甾-1,4-二烯-17β-硫代羟酸酯(0.450g,0.783mmol)在干二氯甲烷(20ml)中的搅拌混合物中,并且在氮保护下在25-30℃将混合物搅拌2小时。将反应混合物用碳酸氢钠溶液(25ml)、水洗涤,干燥,并在真空下浓缩。残余物通过柱层析(己烷中40%的乙酸乙酯)纯化,产生为白色固体的标题化合物。
以类似于实施例18的方式制备化合物IB.6。
实施例19-化合物IB.15
将(Z)-4-氯-丁-2-烯-1-醇(0.691g,6.48mmol)加入6α,9α-二氟-17α-[(2-呋喃甲酰基)氧]-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-硫代羟酸(3.0g,5.87mmol)和无水碳酸钾(0.895g,6.48mmol)在丙酮(60ml)中的搅拌混合物中,并且在氮保护下在25-30℃将混合物搅拌3小时。然后将反应混合物倾倒入水中并用乙酸乙酯萃取。有机层用水洗涤,干燥,并在真空下浓缩。残余物通过柱层析(二氯甲烷中1%的甲醇)纯化,产生为白色固体的标题化合物。
以类似于实施例19的方式制备化合物IB.16、IB.30。利用(E)-4-溴-丁-2-烯-1-醇和式II的合适的硫代酸,通过类似的方式制备化合物B.13、IB.14、IB.17。
实施例20-化合物IB.44
S-[4-(2-乙氧基-1,2-二氧代乙基)氧-(E)-丁-2-烯基]6α,9α-二氟-11β-羟基-16α-甲基-3-氧代-17α-丙酰氧基雄甾-1,4-二烯-17β-硫代羟酸酯
在10-15℃,将草酰氯单乙酯(ethyl oxalyl chloride)(0.352g,2.58mmol)加入S-(4-羟基-(E)-丁-2-烯基)-6α,9α-二氟-11β-羟基-16α-甲基-3-氧代-17α-丙酰氧基雄甾-1,4-二烯-17β-硫代羟酸酯(0.7g,1.29mmol)和三乙胺(0.260g,2.58mmol)在丙酮(20ml)中的搅拌混合物中,并且在氮保护下在25-30℃将混合物搅拌8小时。然后将反应混合物倾倒入水中并用乙酸乙酯萃取。有机层用水洗涤,干燥,并在真空下浓缩。残余物通过柱层析(己烷中35%的乙酸乙酯)纯化,产生为白色固体的标题化合物。
以类似于实施例20的方式制备化合物IB.46。以类似于实施例20的方式分别从IB.15和IB.4制备化合物IB.47和IB.54。
实施例21-化合物IB.42
在25-30℃,将4-溴巴豆酸甲酯(0.191g,1.06mmol)加入6α,9α-二氟-11β-羟基-16α-甲基-3-氧代-17α-丙酰氧基雄甾-1,4-二烯-17β-硫代羟酸(0.5g,1.06mmol)和无水碳酸钾(0.146g,1.06mmol)在N,N-二甲基甲酰胺(10ml)中的搅拌混合物中,并且在氮保护下在25-30℃将混合物搅拌1.5小时。然后将反应混合物倾倒入水中并用乙酸乙酯萃取。有机层用水洗涤,干燥,并在真空下浓缩。残余物通过柱层析(己烷中40%的乙酸乙酯)纯化,产生为白色固体的标题化合物。
以类似于实施例21的方式制备化合物IB.41和IB.43。
实施例22
在10-15℃,将脲-过氧化氢(2.41g,0.0256mol)的N,N-二甲基甲酰胺溶液加入6α,9α-二氟-17α-[(2-呋喃甲酰基)氧]-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-硫代羟酸(13.0g,0.0256mol)在N,N-二甲基甲酰胺(40ml)中的澄清溶液中。将反应混合物在10-15℃搅拌30min,然后倒入冰水中。过滤固体,用水洗涤,并在50-60℃下干燥,产生为白色固体的标题化合物(12.0g,89.48%)。
1H NMR(400 MHz,在CDCl3+DMSO-d6中),δ:1.06(d,J=7.09Hz,3H),1.19(s,3H),1.33-1.38(m,1H),1.55(s,3H),1.58-1.98(m,4H),2.26-2.52(m,4H),3.02-3.06(m,1H),4.32-(br-d,J=8.76Hz,1H),5.14-5.19(br-s,1H),5.38-5.54(m,1H),6.29(s,1H),6.30(d,J=8.71Hz,1H),6.54(dd,J1=3.32Hz,J2=1.53Hz,1H),7.08(d,J=3.37Hz,1H),7.27(d,J=10.30Hz,1H),7.67(s,1H)。
实施例23
6α,9α-二氟-11β-羟基-16α-甲基-3-氧代-17α-丙酰氧基雄甾-1,4-二烯-17β-羰基次磺酸
在10至15℃,将过氧化氢(30vol,60ml)加入6α,9α-二氟-11β-羟基-16α-甲基-3-氧代-17α-丙酰氧基雄甾-1,4-二烯-17β-硫代羟酸(20.0g,42.68mmol)在甲醇(120ml)中的悬浮液中。将反应混合物在环境温度下搅拌1小时。过量的过氧化物用10%焦亚硫酸钠溶液中和,过滤产物,用水洗涤,并干燥,产生为白色固体的标题化合物(19.9g,96.22%)。
1H NMR(400 MHz,在CDCl3+DMSO-d6中),δ:0.98(d,J=7.10Hz,3H),1.08(t,J=7.55Hz,3H),1.12(s,3H),1.25-1.33(m,1H),1.53(s,3H),1.58-1.93(m,4H),2.12-2.47(m,4H),2.33(q,J=7.57Hz,2H),2.95-2.99(m,1H),4.24-4.27(br-d,1H),5.15(br-s,1H),5.36-5.53(m,1H),6.26(s,1H),6.27(dd,J1=10.21Hz,J2=1.68Hz,1H),7.24(d,J=9.73Hz,1H)。
通过类似于实施例23的方法,制备下面的17β-羰基次磺酸:
9α-氟-17α-[(2-呋喃甲酰基)氧]-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-羰基次磺酸。
6α,9α-二氟-11β-羟基-16α-甲基-17α-戊酰氧基(penatanoyloxy)-3-氧代雄甾 -1,4-二烯-17β-羰基次磺酸。
实施例24-化合物IC.3
在0℃,将溴氟甲烷(1.5ml)加入6α,9α-二氟-11β-羟基-16α-甲基-17α-丙酰基-3-氧代雄甾-1,4-二烯-17β-羰基次磺酸(1.5g,3.1mmol)和无水碳酸钾(0.427g,3.1mmol)在丙酮(50ml)中的搅拌混合物中。在氮保护下,在5-10℃,将混合物搅拌1小时。然后将反应混合物倾倒入水中并用乙酸乙酯萃取。有机层用水洗涤,干燥,并在真空下浓缩。残余物通过制备型HPLC纯化,产生为白色固体的标题化合物。
通过如下所示的单晶X-射线证实化合物IC.3的结构: 使用式VI的合适的羰基次磺酸(carbonyl sulfenic acid)和III-C的化合物,以类似于实施例24的方法,制备化合物IC.4、IC.11至IC.14。
实施例25-化合物IC.5
6α,9α-二氟-17α-[(2-呋喃甲酰基)氧]-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-羰基次磺酸(4-氟苯基)甲酯
在25-30℃,将4-氟苄基氯(0.277g,1.91mmol)加入6α,9α-二氟-17α-[(2-呋喃甲酰基)氧]-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-羰基次磺酸(1.0g,1.91mmol)和无水碳酸钾(0.344g,2.49mmol)在N,N-二甲基甲酰胺(15ml)中的搅拌混合物中,并且在氮保护下在25-30℃将混合物搅拌2小时。然后将反应混合物倾倒入水中并用乙酸乙酯萃取。有机层用水洗涤,干燥,并在真空下浓缩。残余物通过从丙酮中结晶进行纯化,产生为白色固体的标题化合物。以类似于实施例25的方式,制备化合物IC.1,IC.2,IC.6-IC.9,IC.15,IC.16,IC.18-IC.23。
实施例26-化合物IC.10
6α,9α-二氟-11β-羟基-16α-甲基-3-氧代-17α-丙酰氧基雄甾-1,4-二烯-17β-羰基次磺酸[2-(4-氯苯基)-2-氧代乙基]酯
在25-30℃,将2-溴-1-(4-氯苯基)乙酮(0.120g,0.51mmol)加入6α,9α-二氟-11β-羟基-16α-甲基-3-氧代-17α-丙酰氧基雄甾-1,4-二烯-17β-羰基次磺酸(0.25g,0.51mmol)和无水碳酸钾(0.070g,0.51mmol)在丙酮(20ml)中的搅拌混合物中,并且在氮保护下在25-30℃将混合物搅拌2小时。然后将反应混合物倾倒入水中并用乙酸乙酯萃取。有机层用水洗涤,干燥,并在真空下浓缩。残余物通过柱层析(己烷中35%的乙酸乙酯)纯化,产生为白色固体的标题化合物。
以类似于实施例26的方式制备化合物IC.17。
实施例27-化合物IB.63
在25-30℃,将氯甲酸甲酯(0.33g,3.48mmol)加入S-(4-羟基-丁-2-炔基)6α,9α-二氟-17α-[(2-呋喃甲酰基)氧]-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-硫代羟酸酯(1.0g,1.74mmol)和三乙胺(0.70g,6.96mmol)在干二氯甲烷(30ml)中的搅拌混合物中。在25-30℃,将混合物搅拌6小时,然后用水洗涤,并在真空下浓缩。残余物通过柱层析(己烷中35%的乙酸乙酯)纯化,产生为白色固体的标题化合物。
以类似于实施例27的方式,制备化合物IB.12,IB.18,IB.19,IB.64-IB.66,IB.89,IB.91,IB.123,IB.125-IB.129,IB.131,IB.134,IB.137-IB.147,IB.149,IB.150,IB.153,IB.154,IB.156。
实施例28-化合物IB.103
S-[4-(N,N-二甲氨基羰氧基)-丁-2-炔基]6α,9α-二氟-17α-[(2-呋喃甲酰基)氧基]-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-硫代羟酸酯
在25-30℃,将N,N-二甲基氨基甲酰氯(0.23g,2.0mmol)加入S-(4-羟基-丁-2-炔基)6α,9α-二氟-17α-[(2-呋喃甲酰基)氧]-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-硫代羟酸酯(1.0g,1.74mmol)和三乙胺(0.70g,6.96mmol)在二氯甲烷(30ml)中的搅拌混合物中。在25-30℃,将混合物搅拌4小时,然后用水洗涤,并在真空下浓缩。残余物通过柱层析(己烷中40%的乙酸乙酯)纯化,产生为白色固体的标题化合物。以类似于实施例28的方式制备化合物IB.129至IB.131。
实施例29-化合物IB.158
将1-氯-4-甲氧基丁-2-炔(0.086g,0.72mmol)加入6α,9α-二氟-17α-[(2-呋喃甲酰基)氧]-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-硫代羟酸(0.350g,0.688mmol)和无水碳酸钾(0.104g,0.756mmol)在丙酮(20ml)中的搅拌混合物中。在氮保护下在25-30℃将混合物搅拌3小时,然后倾倒入水中并用乙酸乙酯萃取。有机层用水洗涤,干燥,并在真空下浓缩。残余物通过柱层析(己烷中35%的乙酸乙酯)纯化,产生为白色固体的标题化合物。
以类似于实施例29的方式制备化合物IB.159、IB.160。
表1-列举了已经合成的式I-A的化合物。 式I-A表-1
编号 | R1 | R2 | R3 | R5 | R6 | P | Q | m1 | Z | 化学名称 |
IA.1 | H | H | H | 乙 氧 基 | 4-氯- 苯基 | H | H | 1 | O | 2-(4-氯苯基)-2-氧代乙基17α-乙氧基羰氧 基-11β-羟基-3-氧代雄甾-1,4-二烯-17β-羧 酸酯。 |
IA.2 | α-CH3 | F | F | 乙 基 | 4-氯- 苯基 | H | H | 1 | o | 2-(4-氯苯基)-2-氧代乙基6α,9α-二氟-11β- 羟基-16α-甲基-3-氧代-17α-丙酰氧基雄甾 -1,4-二烯-17β-羧酸酯 |
IA.3 | α-CH3 | F | F | 乙 基 | 4-氯- 苯基 | H | H | 1 | S | S-[2-(4-氯苯基)-2-氧代乙基]6α,9α-二氟 -11β-羟基-16α-甲基-3-氧代-17α-丙酰氧基 雄甾-1,4-二烯-17β-硫代羟酸酯。 |
IA.4 | H | H | H | 乙 氧 基 | 4-氟- 苯基 | H | H | 1 | O | 2-(4-氟苯基)-2-氧代乙基17α-乙氧基羰氧 基-11β-羟基-3-氧代雄甾-1,4-二烯-17β-羧 酸酯。 |
IA.5 | α-CH3 | F | F | 乙 基 | 4-氟- 苯基 | H | H | 1 | O | 2-(4-氟苯基)-2-氧代乙基6α,9α-二氟-11β- 羟基-16α-甲基-3-氧代-17α-丙酰氧基雄甾 -1,4-二烯-17β-羧酸酯。 |
IA.6 | α-CH3 | F | F | 乙 基 | 4-氟- 苯基 | H | H | 1 | S | S-[2-(4-氟苯基)-2-氧代乙基]6α,9α-二氟 -11β-羟基-16α-甲基-3-氧代-17α-丙酰氧基 |
雄甾-1,4-二烯-17β-硫代羟酸酯。 | ||||||||||
IA.7 | H | H | H | 乙 氧 基 | 2,4-二 氟-苯 基 | H | H | 1 | O | 2-(2,4-二氟苯基)-2-氧代乙基17α-(乙氧基 羰基)氧-11β-羟基-3-氧代雄甾-1,4-二烯 -17β-羧酸酯。 |
IA.8 | H | H | H | 乙 氧 基 | 2,4-二 氯-苯 基 | H | H | 1 | O | 2-(2,4-二氯苯基)-2-氧代乙基17α-(乙氧基 羰基)氧-11β-羟基-3-氧代雄甾-1,4-二烯 -17β-羧酸酯。 |
IA.9 | α-CH3 | F | F | 乙 基 | 2,4-二 氟-苯 基 | H | H | 1 | O | 2-(2,4-二氟苯基)-2-氧代乙基6α,9α-二氟 -11β-羟基-16α-甲基-3-氧代-17α-丙酰氧基 雄甾-1,4二烯-17β-羧酸酯。 |
IA.10 | α-CH3 | F | F | 乙 基 | 2,4-二 氯 苯基 | H | H | 1 | O | 2-(2,4-二氯苯基)-2-氧代乙基6α,9α-二氟 -11β-羟基-16α-甲基-3-氧代-17α-丙酰氧基 雄甾-1,4-二烯-17β-羧酸酯。 |
IA.11 | α-CH3 | F | F | 乙 基 | 2,4-二 氟-苯 基 | H | H | 1 | S | S-2-[(2,4-二氟苯基)-2-氧代乙基]6α,9α-二 氟-11β-羟基-16α-甲基-3-氧代-17α-丙酰氧 基雄甾-1,4-二烯-17β-硫代羟酸酯。 |
IA.12 | H | H | H | 乙 氧 基 | 3,4-二 氯-苯 基 | H | H | 1 | O | 2-(3,4-二氯苯基)-2-氧代乙基17α-乙氧基 羰氧基-11β-羟基-3-氧代雄甾-1,4-二烯 -17β-羧酸酯。 |
IA.13 | α-CH3 | F | F | 乙 基 | 2,4-二 氯-苯 基 | H | H | 1 | S | S-[2-(2,4-二氯苯基)-2-氧代乙基]6α,9α-二 氟-11β-羟基-16α-甲基-3-氧代-17α-丙酰氧 基雄甾-1,4-二烯-17β-硫代羟酸酯。 |
IA.14 | α-CH3 | F | F | 乙 基 | 3,4-二 氯-苯 基 | H | H | 1 | S | S-[2-(3,4-二氯苯基)-2-氧代乙基]6α,9α-二 氟-11β-羟基-16α-甲基-3-氧代-17α-丙酰氧 基雄甾-1,4二烯-17β-硫代羟酸酯。 |
编号 | R1 | R2 | R3 | R5 | R6 | P | Q | m1 | Z | 化学名称 |
1A.15 | α-CH3 | F | F | 乙基 | 3,4-二氯- 苯基 | H | H | 1 | O | 2-(3,4-二氯苯基)-2-氧 代乙基6α,9α-二氟 -11β-羟基-16α-甲基 -3-氧代-17α-丙酰氧基 雄甾-1,4二烯-17β-羧 酸酯。 |
IA.16 | H | H | H | 乙氧 基 | 2-噻吩基 | H | H | 1 | O | 2-氧代-2-(噻吩-2-基) 乙基17α-(乙氧基羰 基)氧-11β-羟基-3-氧 代雄甾-1,4-二烯-17β- 羧酸酯。 |
IA.17 | H | H | H | 乙氧 基 | 5-氯-2-噻 吩基 | H | H | 1 | O | 2-(5-氯噻吩-2-基)-2- 氧代乙基17α-(乙氧基 羰基)氧-11β-羟基-3- 氧代雄甾-1,4-二烯 -17β-羧酸酯。 |
IA.18 | α-CH3 | F | F | 乙基 | 5-氯-2-噻 吩基 | H | H | 1 | O | 2-(5-氯噻吩-2-基)-2- 氧代乙基6α,9α-二 氟-11β-羟基-16α-甲基 -3-氧代-17α-丙酰氧基 雄甾-1,4-二烯-17β-羧 酸酯。 |
IA.19 | H | H | H | 乙氧 基 | 5-甲基- 2-呋喃基 | H | H | 1 | O | 2-(5-甲基呋喃-2- 基)-2-氧代乙基 17α-(乙氧基羰基)氧 -11β-羟基-3-氧代雄甾 -1,4-二烯-17β-羧酸 酯。 |
IA.20 | α-CH3 | F | F | 乙基 | 5-氯-2-噻 吩基 | H | H | 1 | S | S-[2-(5-氯噻吩-2- 基)-2-氧代乙基] 6α,9α-二氟-11β-羟基 |
-16α-甲基-3-氧代 -17α-丙酰氧基雄甾 -1,4-二烯-17β-硫代羟 酸酯。 | ||||||||||
IA.21 | α-CH3 | F | F | 乙基 | 5-甲基-2- 呋喃基 | H | H | 1 | O | 2-(5-甲基呋喃-2- 基)-2-氧代乙基6α,9α- 二氟-11β-羟基-16α-甲 基-3-氧代-17α-丙酰氧 基雄甾-1,4-二烯-17β- 羧酸酯。 |
IA.22 | α-CH3 | F | F | 乙基 | 5-甲基-2- 呋喃基 | H | H | 1 | S | S-[2-(5-甲基呋喃-2- 基)-2-氧代乙基] 6α,9α-二氟-11β-羟基 -16α-甲基-3-氧代 -17α-丙酰氧基雄甾 -1,4-二烯-17β-硫代羟 酸酯。 |
IA.23 | H | H | H | 乙氧 基 | 叔丁基 | H | H | 1 | O | 3,3-二甲基-2-氧代丁 基17α-(乙氧基羰基) 氧-11β-羟基-3-氧代雄 甾-1,4-二烯-17β-羧酸 酯。 |
IA.24 | H | H | H | 乙氧 基 | 甲基 | H | H | 1 | O | 2-氧代丙基17α-(乙氧 基羰基)氧-11β-羟基 -3-氧代雄甾-1,4-二烯 -17β-羧酸酯。 |
IA.25 | α-CH3 | F | F | 乙基 | 叔丁基 | H | H | 1 | O | 3,3-二甲基-2-氧代丁 基6α,9α-二氟-11β-羟 基-16α-甲基-3-氧代 -17α-丙酰氧基雄甾 -1,4-二烯-17β-羧酸 酯。 |
IA.26 | α-CH3 | F | F | 乙基 | 叔丁基 | H | H | 1 | S | S-(3,3-二甲基-2-氧代 丁基)6α,9α-二氟 -11β-羟基-16α-甲基 -3-氧代-17α-丙酰氧基 雄甾-1,4-二烯-17β-硫 代羟酸酯。 |
IA.27 | α-CH3 | F | F | 乙基 | 甲基 | H | H | 1 | S | S-[2-氧代丙基]6α,9α- 二氟-11β-羟基-16α-甲 基-3-氧代-17α-丙酰氧 基雄甾-1,4-二烯-17β- 硫代羟酸酯。 |
IA.28 | α-CH3 | F | F | 乙基 | 甲基 | H | H | 1 | O | 2-氧代丙基6α,9α-二 氟-11β-羟基-16α-甲基 -3-氧代-17α-丙酰氧 基雄甾-1,4-二烯-17β- 羧酸酯。 |
IA.29 | H | H | H | 乙氧 基 | 4-甲氧基- 苯基 | H | H | 1 | O | 2-(4-甲氧苯基)-2-氧代 乙基17α-(乙氧基羰 基)氧-11β-羟基-3-氧 代雄甾-1,4-二烯-17β- 羧酸酯。 |
IA.30 | α-CH3 | F | F | 乙基 | 4-甲氧基- 苯基 | H | H | 1 | O | 2-(4-甲氧苯基)-2-氧代 乙基6α,9α-二氟-11β- 羟基-16α-甲基-3-氧代 -17α-丙酰氧基雄甾 -1,4-二烯-17β-羧酸 酯。 |
IA.31 | α-CH3 | F | F | 乙基 | 4-甲氧基- 苯基 | H | H | 1 | S | S-[2-(4-甲氧苯基)-2- 氧代乙基]6α,9α-二氟 -11β-羟基-16α-甲基 -3-氧代-17α-丙酰氧基 雄甾-1,4-二烯-17β-硫 代羟酸酯。 |
IA.32 | H | H | H | 乙氧 基 | 1-金刚烷 基 | H | H | 1 | O | 2-(金刚烷-1-基)-2-氧 代乙基17α-(乙氧基羰 基)氧-11β-羟基-3-氧 代雄甾-1,4-二烯-17β- 羧酸酯。 |
IA.33 | α-CH3 | F | F | 乙基 | 1-金刚烷 基 | H | H | 1 | O | 2-(金刚烷-1-基)-2-氧 代乙基6α,9α-二氟 -11β-羟基-16α-甲基 -3-氧代-17α-丙酰氧基 雄甾-1,4-二烯-17β-羧 酸酯。 |
IA.34 | α-CH3 | F | F | 乙基 | 1-金刚烷 基 | H | H | 1 | S | S-[2-(金刚烷-1-基)-2- 氧代乙基]6α,9α-二氟 -11β-羟基-16α-甲基 -3-氧代-17α-丙酰氧基 雄甾-1,4-二烯-17β-硫 代羟酸酯。 |
IA.35 | α-CH3 | F | F | 乙基 | 4-三氟甲 氧苯基 | H | H | 1 | S | S-[2-氧代-2-(4-三氟甲 氧苯基)乙基]6α,9α- 二氟-11β-羟基-16α-甲 基-3-氧代-17α-丙酰氧 基雄甾-1,4-二烯-17β- 硫代羟酸酯。 |
表2-列举了已经合成的式I-A-1的化合物以及表-3列举了已经被合成的式LA-2的化合物 式I-A-1 式I-A-2表2
系列 编号 | R1 | R2 | R3 | R5 | R6 | n2 | m1 | Z | 化学名称 |
IA-1.1 | α-CH3 | F | F | 乙 基 | 4-氟苯基 | 2 | 1 | S | S-[1-(4-氟苯甲酰)环戊基]6α,9α-二氟-11β-羟 基-16α-甲基-3-氧代-17α-丙酰氧基-雄甾-1,4-二 烯-17β-硫代羟酸酯。 |
IA-1.2 | α-CH3 | F | F | 乙 基 | 苯基 | 2 | 1 | S | S-[1-苯甲酰环戊基]6α,9α-二氟-11β-羟基-16α- 甲基-3-氧代-17α-丙酰氧基雄甾-1,4-二烯-17β- 硫代羟酸酯。 |
表3
系列 编号 | R1 | R2 | R3 | R5 | n2 | Q | G | m1 | Z | 化学名称 |
IA-2.1 | α-CH3 | F | F | 乙 基 | 2 | H | 苯 基 | 1 | S | S-(1-氧代-1,2,3,4-四氢萘-2-基)6α,9α-二氟-11β-羟 基-16α-甲基-3-氧代-17α-丙酰氧基雄甾-1,4-二烯 -17β-硫代羟酸酯。 |
表4-列举了已经合成的式I-B的化合物 式I-B表-4
系列 编号 | R1 | R2 | R3 | R5 | P | Q | J | K | Z | X | m1 | m2 | m3 | n1 | L | 化学名称 |
IB.1 | α-C H3 | F | F | 乙基 | H | H | H | H | O | ≡ | 1 | 0 | 0 | 1 | OH | 4-羟基-丁-2-炔基 6α,9α-二氟-11β-羟基 -16α-甲基-3-氧代 -17α-丙酰氧基雄甾 -1,4-二烯-17β-羧酸 酯。 |
IB.2 | α-C H3 | F | F | 乙基 | H | H | H | H | S | ≡ | 1 | 0 | 0 | 1 | OH | S-(4-羟基-丁-2-炔 基)6α,9α-二氟-11β- 羟基-16α-甲基-3-氧 代-17α-丙酰氧基雄甾 -1,4-二烯-17β-硫代羟 酸酯。 |
IB.3 | α-C H3 | F | F | 乙基 | H | H | H | H | S | ≡ | 1 | 0 | 0 | 1 | F | S-(4-氟-丁-2-炔 基)6α,9α-二氟-11β- 羟基-16α-甲基-3-氧 代-17α-丙酰氧基雄甾 -1,4-二烯-17β-硫代羟 酸酯。 |
IB.4 | α-C H3 | F | F | 2-呋喃基 | H | H | H | H | S | ≡ | 1 | 0 | 0 | 1 | OH | S-(4-羟基-丁-2-炔 基)6α,9α-二氟 -17α-[(2-呋喃甲酰基) 氧]-11β-羟基-16α-甲 基-3-氧代雄甾-1,4-二 烯-17β-硫代羟酸酯。 |
IB.5 | α-C H3 | F | H | 乙基 | H | H | H | H | S | ≡ | 1 | 0 | 0 | 1 | OH | S-(4-羟基-丁-2-炔 基)9α-氟-11β-羟基 -16α-甲基-3-氧代 -17α-丙酰氧基雄甾 -1,4-二烯-17β-硫代羟 酸酯。 |
IB.6 | α-C H3 | F | F | 2-呋喃基 | H | H | H | H | S | ≡ | 1 | 0 | 0 | 1 | F | S-(4-氟-丁-2-炔 基)6α,9α-二氟 -17α-[(2-呋喃甲酰基) |
氧]-11β-羟基-16α-甲 基-3-氧代雄甾-1,4-二 烯-17β-硫代羟酸酯。 | ||||||||||||||||
IB.7 | α-C H3 | F | F | 异丙基 | H | H | H | H | S | ≡ | 1 | 0 | 0 | 1 | OH | S-(4-羟基-丁-2-炔 基)6α,9α-二氟-11β- 羟基-16α-甲基 -17α-(2-甲基-丙酰氧 基)-3-氧代雄甾-1,4- 二烯-17β-硫代羟酸 酯。 |
IB.8 | α-C H3 | F | F | 环丁基 | H | H | H | H | S | ≡ | 1 | 0 | 0 | 1 | OH | S-(4-羟基-丁-2-炔 基)17α-环丁基羰氧基 -6α,9α-二氟-11β-羟基 -16α-甲基-3-氧代雄 甾-1,4-二烯-17β-硫代 羟酸酯。 |
IB.9 | α-C H3 | F | H | 2-呋喃基 | H | H | H | H | S | ≡ | 1 | 0 | 0 | 1 | OH | S-(4-羟基-丁-2-炔 基)9α-氟-17α-[(2-呋 喃甲酰基)氧]-11β-羟 基-16α-甲基-3-氧代 雄甾-1,4-二烯-17β-硫 代羟酸酯。 |
IB.10 | α-C H3 | F | F | 2-噻吩基 | H | H | H | H | S | ≡ | 1 | 0 | 0 | 1 | OH | S-(4-羟基-丁-2-炔 基)6α,9α-二氟-11β- 羟基-16α-甲基-3-氧 代-17α-[(2-噻吩甲酰 基)氧]-雄甾-1,4-二烯 -17β-硫代羟酸酯。 |
IB.11 | α-C H3 | F | F | 乙基 | H | H | -- | -- | S | ≡ | 1 | 0 | 1 | 0 | -- | S-(丙-2-炔基)6α,9α- 二氟-11β-羟基-16α- 甲基-3-氧代-17α-丙 酰-氧基雄甾-1,4-二烯 -17β-硫代羟酸酯。 |
表5-列举了已经合成的式I-C的化合物 式I-C表-5
系列 编号 | R1 | R2 | R3 | R5 | m1 | R7 | P | Q | 化学名称 |
IC.1 | α-CH3 | F | F | 乙基 | 1 | 4-氟- 苯基 | H | H | 6α,9α-二氟-11β-羟基-16α-甲基-3-氧代-17α-丙酰氧基雄甾 -1,4-二烯-17β-羰基次磺酸(4-氟苯基)甲酯。 |
IC.2 | α-CH3 | F | F | 乙基 | 1 | 3,4-二氯- 苯基 | H | H | 6α,9α-二氟-11β-羟基-16α-甲基-3-氧代-17α-丙酰氧基雄甾 -1,4-二烯-17β-羰基次磺酸(3,4-二氯苯基)甲酯。 |
IC.3 | α-CH3 | F | F | 乙基 | 1 | F | H | H | 6α,9α-二氟-11β-羟基-16α-甲基-3-氧代-17α-丙酰氧基雄甾 -1,4-二烯-17β-羰基次磺酸氟甲酯。 |
IC.4 | α-CH3 | F | F | 2-呋喃 基 | 1 | F | H | H | 6α,9α-二氟-17α-[(2-呋喃甲酰基)氧]-11β-羟基-16α-甲基-3-氧 代雄甾-1,4-二烯-17β-羰基次磺酸氟甲酯。 |
IC.5 | α-CH3 | F | F | 2-呋喃 基 | 1 | 4-氟- 苯基 | H | H | 6α,9α-二氟-17α-[(2-呋喃甲酰基)氧]-11β-羟基-16α-甲基-3-氧 代雄甾-1,4-二烯-17β-羰基次磺酸(4-氟苯基)甲酯。 |
IC.6 | α-CH3 | F | F | 2-呋喃 基 | 1 | 4-三氟- 甲基苯基 | H | H | 6α,9α-二氟-17α-[(2-呋喃甲酰基)氧]-11β-羟基-16α-甲基-3-氧 代雄甾-1,4-二烯-17β-羰基次磺酸(4-三氟甲基苯基)甲酯。 |
IC.7 | α-CH3 | F | F | 2-呋喃 基 | 1 | 4-氯 苯基 | H | H | 6α,9α-二氟-17α-[(2-呋喃甲酰基)氧]-11β-羟基-16α-甲基-3-氧 代雄甾-1,4-二烯-17β-羰基次磺酸(4-氯苯基)甲酯。 |
IC.8 | α-CH3 | F | F | 乙基 | 1 | 4-三氟- 甲基苯基 | H | H | 6α,9α-二氟-11β-羟基-16α-甲基-3-氧代-17α-丙酰氧基雄甾 -1,4-二烯-17β-羰基次磺酸(4-三氟甲基苯基)甲酯。 |
IC.9 | α-CH3 | F | H | 2-呋喃 基 | 1 | 4-氟- 苯基 | H | H | 9α-氟-17α-[(2-呋喃甲酰基)氧]-11β-羟基-16α-甲基-3-氧代雄 甾-1,4-二烯-17β-羰基次磺酸(4-氟苯基)甲酯。 |
IC.10 | α-CH3 | F | F | 乙基 | 1 | 4-氯苯基-羰 基 | H | H | 6α,9α-二氟-11β-羟基-16α-甲基-3-氧代-17α-丙酰氧基雄甾 -1,4-二烯-17β-羰基次磺酸[2-(4-氯苯基)-2-氧代乙基]酯。 |
IC.11 | α-CH3 | F | H | 2-呋喃 基 | 1 | F | H | H | 9α-氟-17α-[(2-呋喃甲酰基)氧]-11β-羟基-16α-甲基-3-氧代雄 甾-1,4-二烯-17β-羰基次磺酸氟甲酯。 |
IC.12 | α-CH3 | F | F | n-C4H9 | 1 | F | H | H | 17α-正丁基羰氧基-6α,9α-二氟-11β-羟基-16α-甲基-3-氧代雄 甾-1,4-二烯-17β-羰基次磺酸氟甲酯。 |
IC.13 | α-CH3 | F | F | 乙基 | 1 | H | H | H | 6α,9α-二氟-11β-羟基-16α-甲基-3-氧代-17α-丙酰氧基雄甾 -1,4-二烯-17β-羰基次磺酸甲酯。 |
IC.14 | α-CH3 | F | F | 2-呋喃 基 | 1 | H | H | H | 6α,9α-二氟-17α-[(2-呋喃甲酰基)氧]-11β-羟基-16α-甲基-3-氧 代雄甾-1,4-二烯-17β-羰基次磺酸甲酯。 |
IC.15 | α-CH3 | F | F | 乙基 | 1 | 苯基 | H | H | 6α,9α-二氟-11β-羟基-16α-甲基-3-氧代-17α-丙酰氧基雄甾 -1,4-二烯-17β-羰基次磺酸苯基甲酯。 |
表-6:所合成的化合物的光谱数据
化合 物编 号 | 1H-NMR(δppm),质量(EI/ES+,m/z) |
IA.1 | 1.19(s,3H),1.29(t,3H,J=7.1Hz),1.45(s,3H),1.5-1.54(m,1H),1.66-1.73(m,3H), 1.81-1.84(m,1H),1.95-2.24(m,6H),2.32-2.36(m,1H),2.56-2.62(m,1H),2.9-3.0(m,1H), 4.1-4.2(q,2h,J=7.1),4.51(br,d,1H,J=2.51Hz),5.07(d,1H,J=16.4Hz),5.62(d,1H, J=16.4Hz),6.17(s,1H),6.27(dd,1H,J1=10.1Hz,J2=1.8Hz),7.27(d,1H,J=10.4Hz),7.47(d, 2H,J=6.9Hz),7.84(d,2H,J=6.9Hz)。质量(ES+):592.9(M+Na)+. |
IA.2 | 0.96(d,3H,J=7.16Hz),1.11-1.15(m,3H),1.24(s,3H),1.55(s,3H),1.67(s,2H),1.71-1.89 (m,3H),2.25-2.40(m,6H),3.3-3.4(m,1H),4.42(br,1H),4.95(d,1H,J=16.6Hz),5.69(d, 1H,J=16.6Hz),5.3-5.37&5.43-5.49(m,1H),6.38(dd,1H,J1=10.14Hz,J2=1.8Hz),6.45(s, 1H),7.16(dd,1H,J1=10.1Hz,J2=1.8Hz),7.49(d,2H,J=8.8Hz),7.56(d,2H,J=8.6Hz)。质 量(ES+):627.0(M+Na)+. |
IA.3 | 0.99(d,3H,J=7.14Hz),1.11-1.14(m,6H),1.53(s,3H),1.62(s,2H),1.7-1.91(m,4H), 2.21-2.29(m,2H),2.34-2.38(m,4H),3.35-3.42(m,1H),4.3(d,1H,J=16.5Hz),4.41(br,1H), 4.48(d,1H,J=16.5Hz),5.30-5.35 & 5.42-5.47(m,1H),6.38(dd,1H,J1=10.15Hz, J2=1.75Hz),6.43(s,1H),7.12(d,1H,J=10.15Hz),7.47(d,2H,J=8.5Hz),7.9(d,2H, J=8.5Hz)。质量(ES+):643.1(M+Na)+. |
IA.4 | 1.16(d,1H,J=3.30Hz),1.20(s,3H),1.29(t,3H,J=7.10Hz),1.48(s,3H),1.54(m,2H),1.70 (m,1H),1.83(m,2H),1.96-2.22(m,5H),2.34(m,1H),2.59(m,1H),2.95(m,1H),4.16(q, 2H,J=7.00Hz),4.52(br,1H),5.08(d,1H,J=16.32Hz),5.63(d,1H,J=16.32Hz),6.02(s,1H), 6.27(dd,1H,J1=10.59Hz,J2=1.67Hz),7.17(dd,2H,J1=J2=8.55Hz),7.28(d,1H,J=10.19Hz), 7.94(dd,2H,J1=8.76,J2=5.31)。质量(EI):554 |
IA.5 | 0.96(s,3H),1.13(t,3H,J=7.55Hz),1.24(s,3H),1.30(m,1H),1.55(s,3H),1.82(m,2H), 2.05(m,2H),2.20(b r,1H),2.25-2.50(m,6H),3.35(m,1H),4.41(d,1H,J=8.52Hz),5.00(d, 1h,J=16.53),5.33 & 5.46(m,1H),5.69(d,1H,J=16.53Hz),6.38(1H,dd,J1=10.15Hz, J2=1.64Hz),6.44(s,1H),7.18(dd,2H,J1=J2=8.50Hz),7.95(dd,2H,J1=8.70Hz,J2=5.30Hz)。 质量(ES+):611.1(M+Na)+. |
IA.6 | 0.99(d,3H,J=7.15Hz),1.13(m,6H),1.25(s,1H),1.33(m,1H),1.53(s,3H),1.86(m,3H), 2.26(m,2H),2.39(m,4H),3.39(m,1H),4.32(d,1H,J=16.48Hz),4.41(d,1H,J=8.92Hz), 4.48(d,1H,J=16.49Hz),5.32 & 5.44(m,1H),6.38(dd,1H,J1=10.15Hz,J2=1.69Hz),6.44 (s,1H),7.12(dd,1H,J1=10.19Hz,J2=0.95Hz),7.17(dd,2H,J1=J2=8.50Hz),8.05(dd,2H, J1=10.26Hz,J2=5.35Hz)。质量(ES+):627.1(M+Na)+. |
IA.7 | 1.18(dd,2H,J1=11.44Hz,J2=3.21Hz),1.21(s,3H),1.29(t,3H,J=7.11Hz),1.48(s,3H), 1.52(m,1H),1.66-1.84(m,2H),1.95-2.22(m,6H),2.32-2.36(m,1H),2.91-2.98(m,1H), 4.16(q,2H,J=7.14Hz),4.52(s,1H),5.00(dd,1H,J1=17.35Hz,J2=Hz3.61),5.48(dd,1H, J1=17.35Hz,J2=3.61Hz),6.02(s,1H),6.22(dd,1H,J110.09Hz,J2=1.73Hz),6.92(t,1H, J=6.67Hz),7.00(1H,t,J=6.67Hz),7.29(1H,d,J=10.15Hz),8.01(dd,1H,J1=8.25Hz, J2=6.75Hz)。质量(ES+):595.1(M+Na)+. |
化合物 编号 | 1H-NMR(δppm),质量(EI/ES+,m/z) |
IA.8 | 1.13(s,3H),1.16(dd,2H,J1=11.37Hz,J2=3.2Hz),1.28(t,3H,J=7.13Hz),1.47(s,3H), 1.50-1.52(m,1H),1.64-1.68(m,1H),1.80-1.83(m,1H),1.91-2.20(m,6H),2.33(dd,1H, J1=13.36Hz,J2=2.80Hz),2.53-2.61(m,1H),2.88-2.95(m,1H),4.14(q,2H,J=7.12Hz),4.51 (s,1H),5.00(d,1H,J=16.75Hz),5.41(d,1H,J=16.75Hz),6.02(s,1H),6.26(dd,1H, J1=10.01,J2=1.78Hz),7.27(d,1H,J=10.09Hz),7.36(dd,1H,J1=8.38Hz,J21.93Hz),7.47(d, 1H,J=1.89Hz),7.62(d,1H,J=8.37Hz)。质量(ES+):627.0(M+Na)+. |
IA.9 | 0.96(d,3H,J=7.14Hz),1.14(t,3H,J=7.57Hz),1.26(s,3H),1.29-1.34(m,3H),1.56(s,3H), 1.71-1.88(m,4H),2.02-2.05(m,1H),2.25-2.50(m,6H),3.33-3.38(m,1H),4.42(d,1H, J=8.87Hz),4.92(dd,1H,J1=17.59Hz,J2=3.07Hz),5.35 & 5.46(m,1H),5.56(dd,1H, J1=17.59Hz,J2=3.07Hz),6.38((dd,1H,J1=10.14Hz,J2=1.70Hz),6.44(s,1H),6.90-7.04 (m,1H),7.15(d,1H,J=10.12Hz),8.00(dd,1H,J1=15.04Hz,J2=8.43Hz)。质量(ES+): 629.0(M+Na)+. |
IA.10 | 0.94(d,3H,J=6.91Hz),1.12(t,3H,J=7.51Hz),1.18(s,3H),1.24-1.32(m,2H),1.55(s,3H), 1.71-1.96(m,4H),2.27-2.48(m,5H),3.32(s,1H),4.40(d,1H,J=7.18Hz),4.90(d,1H, J=16.85Hz),5.33(m,0.5H),5.46(d,1.5H,J=16.87Hz),6.38(d,1H,J=10.07Hz),6.44 (s,1H),7.15(d,1H,J=9.95Hz),7.37(d,1H,J=8.30Hz),7.49(s,1H),7.64(d,1H,J=8.33)。质 量(ES+):661.0(M+Na)+. |
IA.11 | 0.98(d,3H,J=7.13Hz),1.10-1.13(m,6H),1.26-1.35(m,2H),1.54(s,3H),1.72-2.01 (m,4H),2.23-2.46(m,5H),3.37(m,1H),4.92(dd,1H,J1=17.43Hz,J2=2.69Hz),4.43(dd, 2H,J1=17.44Hz,J22.76Hz),5.33 & 5.45(m,1H),6.37(dd,1H,J1=10.13Hz,J2=1.73Hz), 6.43(s,1H),6.89-7.01(m,2H),7.16(dd,1H,J1=10.14Hz,J2=1.05Hz),7.94(dd,1H, J1=15.09hz,J2=8.50Hz)。质量(ES+):645.0(M+Na)+. |
IA.12 | 1.15(d,1H,J=3.26Hz),1.17(s,4H),1.29(t,3H,J=7.13Hz),1.48(s,3H),1.51-1.54(m,1H), 1.66-1.73(m,2H),1.81-1.84(m,1H),1.95-2.22(m,5H),2.34(dd,1H,J1=13.41Hz, J2=2.71Hz),2.56-2.62(m,1H),2.90-2.97(m,1H),4.15(q,2H,J=7.15Hz),4.52(s,1H),5.06 (d,1H,J=16.43Hz),5.56(d,1H,J=16.43Hz),6.02(s,1H),6.27(dd,1H,J1=10.08Hz, J2=1.70Hz),7.29(d,1H,J=10.08Hz),7.59(d,1H,J=8.34Hz),7.73(dd,1H,J1=8.35Hz, J2=1.92Hz),7.99(d,1H,J=1.88Hz)。质量(ES+):627.0(M+Na)+. |
IA.13 | 0.97(d,3H,J=7.16Hz),1.05(s,3H),1.12(t,3H,J=7.58Hz),1.28-1.35(m,2H),1.53(s,3H), 1.72-1.94(m,3H),2.24-2.42(m,6H),3.35(m,1H),4.21(d,1H,J=16.84Hz),4.34(d,1H, J=6.84Hz),5.32 & 5.44(m,1H),6.38(dd,1H,J1=10.14hz,J2=1.78Hz),6.43(s,1H),7.11 (dd,1H,J1=10.12Hz,J2=1.22Hz),7.35(dd,1H,J1=8.34Hz,J2=1.92Hz),7.46(d,1H, J=8.33Hz)。质量(ES+):677.0(M+Na)+. |
IA.14 | 0.99(3H,d,J=7.10Hz),1.10(s,3H),1.12(t,3H,J=7.57Hz),1.33(m,1H),1.53(s,3H), 1.73-1.97(m,5H),2.20-2.46(m,5H),3.37(m,1H),4.28(d,2H,J=16.38Hz),4.41(d,2H, J=15.93Hz),5.32&5.44(m,1H),6.36(d,1H,J=10.14Hz),6.43(s,1H),7.13(d,1H, J=10.14hz),7.58(d,1H,J=8.35Hz),7.83(dd,1H,J1=8.23Hz,J2=1.66Hz),8.08(d,1H, J=1.71Hz)。质量(ES+):677.0(M+Na)+. |
1A.15 | 0.96(d,3H,J=7.10Hz),1.13(t,3H,J=7.56Hz),1.22(s,3H),1.26-1.33(m,2H),1.55(s,3H), 1.71-1.90(m,3H),2.00(d,1H,J=14.88Hz),2.27-2.50(m,5H),3.34(m,1H),4.41(d,1H, J=8.73Hz),4.96(d,1H,J=16.66Hz),5.33 & 5.45(m,1H),5.64(d,1H,J=16.59Hz),6.38(d, 1H,J=10.14Hz),6.44(s,1H),7.14(d,1H,J=10.14Hz),7.59(d,1H,J=8.35Hz),8.01(s,1H)。 |
IA.16 | 1.15(m,2H),1.19(s,3H),1.29(t,3H,J=7.13Hz),1.61(s,3H),1.66-1.84(m,2H),1.95-2.22 (m,6H),2.32-2.36(m,1H),2.55-2.63(m,2H),2.92-2.98(m,1H),4.15(q,2H,J=7.04Hz), 4.51(br,1H),5.00(d,1H,J=16.00Hz),5.58(d,1H,J=16.00Hz),6.02(s,1H),6.27(dd,1H, J1=10.09Hz,J2=1.74Hz),7.18(t,1H,J=3.94Hz),7.29(s,1H),7.72(d,1H,J=4.92Hz),7.75 (d,1H,J=3.82Hz)。质量(ES+):565.1(M+Na)+. |
IA.17 | 1.16(s,3H),1.19(m,2H),1.28(t,3H,J=7.13Hz),1.45(m,2H),1.47(s,3H),1.67-2.38(m, 6H),2.51-2.67(m,1H),2.88-3.00(m,1H),4.14(q,2H,J1=14.24Hz,J2=7.11Hz),4.51(br, 1H),4.94(d,1H,J=15.95Hz),5.49(d,1H,J=15.98Hz),6.02(s,1H),6.27(dd,1H, J1=10.07Hz,J2=1.72Hz),7.00(d,1H,J=4.08Hz),7.27(d,1H,J=9.96Hz),7.54(d,1H, J=4.09Hz)。质量(ES+):599.0(M+Na)+. |
IA.18 | 0.95(d,3H,J=7.14Hz),1.13(t,3H,J=7.56Hz),1.20(s,3H),1.26-1.36(m,1H),1.54(s,3H), 1.77-2.04(m,4H),2.25-2.43(m,6H),3.30-3.37(m,1H),4.40(d,1H,J=9.64Hz),4.85(d, 1H,J=16.19Hz),5.28 & 5.51(m,1H),5.56(d,1H,J=16.17Hz),6.35-6.44(m,2H),7.00(d, 1H,J=4.09Hz),7.14(d,1H,J=10.02Hz),7.54(d,1H,J=4.08Hz)。质量(ES+): 633.0(M+Na)+. |
IA.19 | 1.17(m,2H),1.18(s,3H),1.28(t,3H,J=7.11Hz),1.47(s,5H),1.70-2.38(m,8H),2.41(s, 3H),2.51-2.66(m,1H),2.88-3.01(m,1H),4.15(q,2H,J1=14.21Hz,J2=7.09Hz),4.49(br, 1H),4.89(d,1H,J=16.20Hz),5.49(d,1H,J=16.21Hz),6.02(s,1H),6.21(d,1H, J=3.51Hz),6.27(dd,1H,J1=10.11Hz,J2=1.72Hz),7.19(d,1H,J=3.46Hz),7.28(d,1H, J=9.26Hz)。质量(EI):540 |
IA.20 | 0.99(d,3H,J=7.35Hz),1.10-1.16(m,6H),1.21-1.38(m,1H),1.53(s,3H),1.69-2.02(m, 4H),2.16-2.49(m,6H),3.34-3.46(m,1H),4.17(d,1H,J=16.03Hz),4.35(d,1H, J=16.01Hz),4.43(br,1H),5.28 & 5.51(m,1H),6.37(d,1H,J=10.33Hz),6.99(d,1H, J=4.03Hz),7.16(d,1H,J=10.03hz),7.65(d,1H,J=4.04Hz)。质量(ES+):649.0(M+Na)+. |
IA.21 | 0.95(d,3H,J=7.13Hz),1.13(t,3H,J=7.56Hz),1.22(s,3H),1.54(s,3H),1.70-1.88(m,2H), 2.03-2.08(m,1H),2.25-2.51(m,8H),2.40(s,3H),3.30-3.38(m,1H),4.39(d,1H, J=8.28Hz),4.80(d,1H,J=16.31Hz),5.28 & 5.50(m,1H),5.52(d,1H,J=16.33Hz),6.21(d, 1H,J=2.99Hz),6.37(dd,1H,J1=10.12Hz,J2=1.77Hz),6.43(s,1H),7.15-7.20(m,2H)。质 量(EI):574 |
IA.22 | 0.98(d,3H,J=7.13Hz),1.09-1.16(m,6H),1.22-1.37(m,1H),1.53(s,3H),1.69-2.56(m, 10H),2.41(s,3H),3.36-3.43(m,1H),4.12(d,1H,J=16.31Hz),4.33(d,1H,J=16.33Hz), 4.43(b r,1H),5.28&5.52(m,1H),6.21(d,1H,J=3.12Hz),6.34-6.43(m,2H),7.18(dd,1H, J1=10.04Hz,J2=1.03Hz),7.27(d,1H,J=3.60Hz)。质量(ES+):613.1(M+Na)+. |
IA.23 | 1.17(s,3H),1.20(s,1H),1.21(s,9H),1.28(t,3H,J=7.12Hz),1.43(s,1H),1.47(s,3H), 1.63-2.97(m,12H),4.14(q,2H,J1=14.26Hz,J2=7.12Hz),4.49(br,1H),4.63(d,1H, J=16.68Hz),5.23(d,1H,J=16.69Hz),6.01(s,1H),6.27(dd,1H,J1=10.10Hz,J2=1.84Hz), 7.27(d,1H,J=9.73Hz)。质量(EI):516 |
IA.24 | 1.13(s,3H),1.18-1.25(m,3H),1.28(t,3H,J=7.12Hz),1.47(s,3H),1.55-2.16(m,8H),2.18 (s,3H),2.36-2.96(m,3H),4.14(q,2H,J=7.13Hz),4.50(d,1H,J=16.83Hz),4.51(m,1H), 4.92(d,1H,J=16.84Hz),6.02(s,1H),6.26(dd,1H,J1=10.09Hz,J2=1.82Hz),7.28(d,1H, J=10.10Hz)。质量(EI):474 |
IA.25 | 0.94(d,3H,J=7.17Hz),1.12(t,3H,J=7.56Hz),1.21(s,12H),1.26-1.29(m,1H),1.54(s, 3H),1.77-2.41(m,10H),3.28-3.35(m,1H),4.38(br,1H),4.54(d,1H,J=16.98Hz),5.28 & 5.52(m,1H),5.30(d,1H,J=16.91Hz),6.38(dd,1H,J1=10.10Hz,J2=1.73Hz),6.43(s,1H), 7.17(dd,1H,J1=10.05Hz,J2=1.10Hz)。质量(ES+):573.2(M+Na)+. |
IA.26 | 0.98(d,3H,J=7.12Hz),1.12(s,3H),1.12(t,3H,J=7.54Hz),1.24(s,9H),1.23-1.34(m,1H), 1.54(s,3H),1.75-2.50(m,10H),3.34-3.42(m,1H),3.89(d,1H,J=17.40Hz),4.14(d,1H, J=17.38Hz),4.38-4.42(br,1H),5.28 & 5.52(m,1H),6.37(dd,1H,J1=10.20Hz,J2=1.64Hz), 6.43(s,1H),7.17(d,1H,J=9.96Hz)。质量(ES+):589.1(M+Na)+. |
IA.27 | 0.99(d,3H,J=7.13Hz),1.10(s,3H),1.12(t,3H,J=7.55Hz),1.20-1.39(m,2H),1.53(s,3H), 1.69-1.97(m,4H),2.22-2.42(m,8H),3.33-3.40(m,1H),3.72(d,1H,J=16.52Hz),3.83(d, 1H,J=16.51Hz),4.40(br,1H),5.28 & 5.50(m,1H),6.38(dd,1H,J1=10.08Hz,J2=1.28Hz), 6.43(s,1H),7.13(dd,1H,J1=10.08Hz,J2=1.37Hz)。质量(ES+):547.1(M+Na)+. |
化合物 编号 | 1H-NMR(δppm),质量(EI/ES+,m/z) |
IB.90 | 1.06(d,J=7.14Hz,3H),1.17(s,3H),1.34-1.40(m,1H),1.55(s,3H),1.76-1.97(m,3H),2.06(s, 3H),2.28-2.54(m,4H),3.41-3.46(m,1H),3.67-3.75(m,2H),4.00(dd,J1=18.22Hz, J2=5.46Hz,1H),4.09(dd,J1=18.22Hz,J2=5.84Hz,1H),4.41(d,J=5.81Hz,1H),4.71(s,2H), 5.32-5.49(m,1H),6.11(s,1H),6.39(dd,J1=10.16Hz,J2=1.79Hz,1H),6.45(s,1H),6.50(dd, J1=3.45Hz,J2=1.77Hz,1H),7.12(d,J=3.51Hz,1H),7.19(dd,J1=10.09Hz,J2=0.96Hz,1H), |
7.58(d,J=0.90Hz,1H)。质量(ES+):696.13(M+Na)+ | |
IB.91 | 0.96(d,J=6.72Hz,3H),1.05(d,J=7.15Hz,3H),1.19(s,3H),1.35-1.41(m,1H),1.55(s,3H), 1.78-2.02(m,4H),2.30-2.63(m,5H),3.41-3.45(m,1H),3.70(d,J=16.81Hz,1H),3.76(d, J=16.76Hz,1H),3.93(d,J=6.80Hz,2H),4.44-4.46(m,1H),4.66(d,J=15.53Hz,1H),4.71(d, J=15.50Hz,1H),5.33-5.49(m,1H),6.40(dd,J1=10.13Hz,J2=1.67Hz,1H),6.46(s,1H), 6.94(d,J=4.00Hz,1H),7.15(d,J=10.22Hz,1H),7.53(d,J=4.01Hz,1H)。质量(ES+): 747.0(M+Na)+ |
IB.92 | 1.05(d,J=7.14Hz,3H),1.18(d,J=6.98Hz,3H),1.19(d,J=7.13Hz,3H),1.22(s,3H), 1.35-1.41(m,1H),1.56(s,3H),1.78-2.00(m,3H),2.28-2.63(m,5H),3.23(d,J=3.19Hz,1H), 3.40-3.45(m,1H),3.67-3.75(m,2H),3.45-3.47(m,1H),3.49-3.77(m,2H),5.33-5.50(m,1H), 6.41(dd,J1=10.15Hz,J2=1.79Hz,1H),6.46(s,1H),6.93(d,J=4.0Hz,1H),7.18(dd, J1=10.14Hz,J2=1.08Hz,1H),7.53(d,J=4.08Hz,1H)。质量(ES+):717.12(M+Na)+ |
IB.93 | 1.06(d,J=7.16Hz,3H),1.17(s,3H),1.33(t,J=7.12Hz,3H),1.36-1.40(m,1H),1.55(s,3H), 1.71-1.97(m,3H),2.28-2.48(m,4H),2.71(s,1H),3.42-3.48(m,1H),3.68(d,J=16.79Hz,1H), 3.77(d,J=16.60Hz,1H),4.25-4.30(m,2H),4.44(m,1H),4.68(d,J=15.47Hz,1H),4.81(d, J=15.45Hz,1H),5.32-5.49(m,1H),6.21(d,J=12.01Hz,1H),6.32(d,J=11.98Hz,1H), 6.40(dd,J1=10.10Hz,J2=1.75Hz,1H),6.45(s,1H),6.50(dd,J1=3.47Hz,J2=1.75Hz,1H), 7.13(d,J=3.42Hz,1H),7.19(dd,J1=10.25Hz,J2=0.81Hz,1H),7.59(d,J=0.88Hz,1H)。质量 (ES+):723.22(M+Na)+ |
IB.94 | 1.06(d,J=7.17Hz,3H),1.18(s,3H),1.35-1.41(m,1H),1.56(s,3H),1.74-1.99(m,3H), 2.28-2.47(m,4H),2.63-2.69(m,4H),2.93(s,1H),3.43-3.47(m,1H),3.66(d,J=16.86Hz,1H), 3.70(s,3H),3.76(d,J=17.21Hz,1H),4.45(d,J=8.60Hz,1H),4.59(d,J=15.38Hz,1H), 4.68(d,J=15.45Hz,1H),5.33-5.50(m,1H),6.41(dd,J1=10.15Hz,J2=1.76Hz,1H),6.46(s,1H), 6.51(dd,J1=3.45Hz,J2=1.64Hz,1H),7.13(d,J=3.43Hz,1H),7.19(d,J=9.97Hz,1H),7.59(d, J=0.73Hz,1H)。质量(ES+):711.19(M+Na)+ |
IB.95 | 1.06(d,J=7.07Hz,3H),1.18(s,3H),1.23(d,J=6.20Hz,3H),1246(d,J=6.25Hz,3H), 1.35-1.41(m,1H),1.56(s,3H),1.74-2.00(m,3H),2.28-2.51(m,4H),2.58-2.67(m,4H),3.00(s, 1H),3.43-3.47(m,1H),3.65(d,J=16.97Hz,1H),3.76(d,J=17.57Hz,1H),4.46(d,J=8.05Hz, 1H),4.59(d,J=15.43Hz,1H),4.72(d,J=15.40Hz,1H),4.96-5.06(m,1H),5.33-5.49(m,1H), 6.41(dd,J1=10.20Hz,J2=1.24Hz,1H),6.46(s,1H),6.51(dd,J1=3.13Hz,J2=1.24Hz,1H), 7.13(d,J=3.33Hz,1H),7.19(d,J=10.11Hz,1H),7.59(s,1H)。质量(ES+):739.31(M+Na)+ |
IB.96 | 0.92(d,J=6.64Hz,6H),1.06(d,J=6.64Hz,3H),1.18(s,3H),1.36-1.41(m,1H),1.56(s,3H), 1.74-2.06(m,4H),2.29-2.51(m,4H),2.66-2.69(m,4H),2.99(s,1H),3.43-3.45(m,1H), 3.66(d,J=16.76Hz,1H),3.77(d,J=16.64Hz,1H),3.88(d,J=6.57Hz,2H),4.46(d,J=6.66Hz, 1H),4.59(d,J=15.40Hz,1H),4.73(d,J=15.33Hz,1H),5.33-5.49(m,1H),6.41(d,J1=10.11Hz, 1H),6.45(s,1H),6.50(dd,J1=2.62Hz,J2=1.21Hz,1H),7.13(d,J=3.43Hz,1H),7.19(d, J=10.11Hz,1H),7.59(s,1H)。质量(ES+):753.35(M+Na)+ |
IB.97 | 0.92(t,J=7.32Hz,3H),1.05(d,J=7.15Hz,3H),1.18(s,3H),1.20-1.38(m,5H),1.40-1.62(m, 4H),1.77-2.00(m,3H),2.25-2.50(m,4H),2.61-2.69(m,4H),2.97(s,1H),3.42-3.47(m,1H), 3.65(d,J=16.71Hz,1H),3.76(d,J=16.87Hz,1H),4.10(t,J=6.71Hz,2H),4.45(d, J=8.59Hz,1H),4.59(d,J=15.45Hz,1H),4.72(d,J=15.43Hz,1H),5.32-5.49(m,1H),6.39(dd, J1=10.16Hz,J2=1.78Hz,1H),6.46(s,1H),6.50(dd,J1=3.74Hz,J2=1.47Hz,1H),7.13(d, J=3.44Hz,1H),7.19(dd,J1=10.10Hz,J2=0.91Hz,1H),7.59(d,J=1.08Hz,1H)。质量(ES+): 753.18(M+Na)+ |
IB.98 | 1.06(d,J=7.12Hz,3H),1.21(s,3H),1.31(s,6H),1.35-1.41(m,1H),1.56(s,3H),1.77-2.01(m, 3H),2.29-2.53(m,4H),2.91(d,J=2.26Hz,1H),3.43-3.47(m,1H),3.58-3.64(m,2H),3.66(d, J=17.24Hz,1H),3.76(d,J=16.76Hz,1H),4.45-4.47(m,1H),4.57(d,J=15.36Hz,1H), 4.78(d,J=15.36Hz,1H),5.34-5.50(m,1H),6.40(dd,J1=10.15Hz,J2=1.46Hz,1H),6.45(s, 1H),6.50(dd,J1=3.28Hz,J2=1.48Hz,1H),7.14(d,J=3.49Hz,1H),7.18(dd,J=10.12Hz,1H), 7.59(s,1H)。质量(ES+):715.02(M+Na)+ |
IB.99 | 0.94(d,J=6.70Hz,6H),1.06(d,J=7.12Hz,3H),1.17(s,3H),1.25-1.40(m,1H),1.55(s,3H), 1.73-1.99(m,4H),2.28-2.46(m,4H),2.73(s,1H),3.43-3.47(m,1H),3.67(d,J=16.91Hz,1H), 3.78(d,J=17.01Hz,1H),3.99(d,J=6.69Hz,2H),4.44(d,J=8.42Hz,1H),4.67(d,J=15.51Hz, 1H),4.81(d,J=15.46Hz,1H),5.32-5.49(m,1H),6.22(d,J=12.05Hz,1H),6.34(d,J=12.03Hz, 1H),6.39(dd,J1=10.13Hz,J2=1.65Hz,1H),6.45(s,1H),6.50(dd,J1=3.57Hz,J2=1.85Hz,1H), 7.13(d,J=3.44Hz,1H),7.19(d,J=10.20Hz,1H),7.59(d,J=0.67Hz,1H)。质量(ES+): |
751.16(M+Na)+ | |
IB.100 | 1.06(d,J=7.15Hz,3H),1.16(s,3H),1.25-1.41(m,1H),1.56(s,3H),1.77-1.96(m,3H), 2.28-2.49(m,4H),2.71(s,1H),3.41-3.45(m,1H),3.67(d,J=16.72Hz,1H),3.77(d, J=16.87Hz,1H),3.82(s,3H),4.46(m,1H),4.74(d,J=15.44Hz,1H),4.80(d,J=15.44Hz,1H), 5.32-5.49(m,1H),6.42(dd,J1=10.16Hz,J2=1.79Hz,1H),6.46(s,1H),6.50(dd,J1=3.45Hz, J2=1.76Hz,1H),6.86(d,J=15.85Hz,1H),6.90(d,J=15.82Hz,1H),7.13(d,J=3.51Hz,1H), 7.20(dd,J1=10.00Hz,J2=1.00Hz,1H),7.59(d,J=0.73Hz,1H)。质量(ES+):709.11(M+Na)+ |
IB.101 | 0.96(d,J=6.59Hz,6H),1.05(d,J=7.115Hz,3H),1.20(s,3H),1.35-1.41(m,1H),1.56(s,3H), 1.77-2.01(m,3H),2.052.12(m,1H),2.21-2.52(m,6H),3.07(d,J=2.84Hz,1H),3.43-3.47(m, 1H),3.65(d,J=16.86Hz,1H),3.77(d,J=16.79Hz,1H),4.45(d,J=8.63Hz,1H),4.52(d, J=15.42Hz,1H),4.73(d,J=15.34Hz,1H),5.33-5.48(m,1H),6.40(dd,J1=10.12Hz, J2=1.71Hz,1H),6.45(s,1H),6.50(dd,J1=3.43Hz,J2=1.61Hz,1H),7.13(d,J=3.43Hz,1H), 7.19(dd,J=10.19Hz,1H),7.58(d,J=0.85Hz,1H)。质量(ES+):681.0(M+Na)+ |
IB.102 | 0.90(q,J=7.40Hz,3H),1.05(d,J=7.14Hz,3H),1.23(s,3H),1.35-1.41(m,1H),1.50-1.65(m, 4H),1.57(s,3H),1.77-2.01(m,3H),2.21-2.55(m,5H),3.31(d,J=2.47Hz,1H),3.44-3.47(m, 1H),3.64(d,J=16.73Hz,1H),3.76(d,J=16.70Hz,1H),4.43-4.46(m,1H),4.49(d, J=15.39Hz,1H),4.78(d,J=15.38Hz,1H),5.34-5.50(m,1H),6.40(dd,J1=10.08Hz, J2=1.62Hz,1H),6.45(s,1H),6.50(dd,J1=3.37Hz,J2=1.57Hz,1H),7.13(d,J=3.45Hz,1H), 7.19(dd,J=10.16Hz,1H),7.59(s,1H)。质量(ES+):695.0(M+Na)+ |
IB.103 | 1.05(d,J=7.18Hz,3H),1.23(s,3H),1.34-1.40(m,1H),1.56(s,3H),1.77-2.08(m,3H), 2.17-2.53(m,4H),2.92(s,6H),3.44-3.48(m,1H),3.64(d,J=16.62Hz,1H),3.76(d, J=16.16Hz,1H),4.01(d,J=3.45Hz,1H),4.41-4.43(m,1H),4.49(d,J=15.61Hz,1H),4.76(d, J=15.59Hz,1H),5.33-5.50(m,1H),6.39(dd,J1=10.11Hz,J2=1.75Hz,1H),6.45(s,1H), 6.50(dd,J1=3.47Hz,J2=1.74Hz,1H),7.14(d,J=3.40Hz,1H),7.18(dd,J1=10.16Hz, J2=0.91Hz,1H),7.59(s,1H)。质量(ES+):668.0(M+Na)+ |
IB.104 | 1.06(d,J=7.12Hz,3H),1.21(s,3H),1.35-1.41(m,1H),1.56(s,3H),1.79(s,3H),1.80(s,3H), 1.80-1.98(m,3H),2.28-2.52(m,4H),2.70(d,J=2.16Hz,1H),3.42-3.46(m,1H),3.67-3.77(m, 2H),3.44-3.46(m,1H),4.62-4.85(m,2H),5.33-5.49(m,1H),6.39(dd,J1=10.15Hz, J2=1.70Hz,1H),6.45(s,1H),6.50(dd,J1=3.44Hz,J2=1.71Hz,1H),7.12(dd,J=3.42Hz,1H), 7.16(dd,J1=10.07Hz,J2=0.93Hz,1H),7.58(s,1H)。质量(ES+):679.0 |
化合物 编号 | 1H-NMR(δppm),质量(EI/ES+,m/z) |
IB.105 | 0.90(d,J=6.31Hz,3H),0.91(d,J=6.24Hz,3H),1.06(d,J=7.14Hz,3H),1.20(s,3H), 1.35-1.41(m,1H),1.47-1.59(m,3H),1.56(s,3H),1.77-2.00(m,3H),2.29-2.52(m,4H), 2.35(t,J=7.72Hz,2H),3.10(d,J=2.65Hz,1H),3.43-3.46(m,1H),3.65(d,J=16.80Hz,1H), 3.77(d,J=16.81Hz,1H),4.44-4.46(m,1H),4.53(d,J=15.38Hz,1H),4.71(d,J=15.33Hz, 1H),5.33-5.50(m,1H),6.39(dd,J1=10.16Hz,J2=1.74Hz,1H),6.45(s,1H),6.50(dd, J1=3.43Hz,J2=1.77Hz,1H),7.13(d,J=3.60Hz,1H),7.18(dd,J1=10.22Hz,J2=0.72Hz,1H), 7.59(s,1H)。质量(ES+):673.0 |
IB.106 | 1.06(d,J=7.18Hz,3H),1.17(s,3H),1.35-1.41(m,1H),1.55(s,3H),1.74-1.97(m,3H), 2.28-2.48(m,4H),2.65(s,1H),2.69-2.77(m,4H),3.43-3.47(m,1H),3.67(d,J=16.80Hz,1H), 3.76(d,J=16.76Hz,1H),4.45(d,J=8.68Hz,1H),4.61(d,J=15.48Hz,1H),4.74(d, J=15.38Hz,1H),5.32-5.49(m,1H),5.71(d,J=50.60Hz,2H),6.41(dd,J1=10.18Hz,J2=1.81Hz, 1H),6.45(s,1H),6.51(dd,J1=3.49Hz,J2=1.64Hz,1H),7.13(d,J=3.29Hz,1H),7.18(dd, J1=10.16Hz,J2=0.91Hz,1H),7.59(d,J=0.79Hz,1H)。质量(ES+):729.28(M+Na)+ |
IB.106 | 1.06(d,J=7.17Hz,3H),1.17(s,3H),1.25-1.41(m,1H),1.54(s,3H),1.77-1.98(m,3H), 2.28-2.49(m,5H),3.42-3.47(m,1H),3.69(d,J=16.78Hz,1H),3.78(d,J=16.84Hz,1H), 4.44(d,J=8.74Hz,1H),4.66(d,J=17.09Hz,1H),4.84(d,J=17.31Hz,1H),5.32-5.49(m,1H), 5.78(dd,J1=50.72Hz,J2=1.89Hz,1H),5.82(dd,J1=50.31Hz,J2=1.91Hz,1H),6.34(d, J=12.00Hz,1H),6.38(d,J=12.14Hz,1H),6.39(dd,J1=3.46Hz,J2=1.60Hz,1H),6.45(s,1H), 6.51(dd,J1=3.46Hz,J2=1.60Hz,1H),7.13(d,J=3.42Hz,1H),7.17(d,J=10.16Hz,1H), 7.59(d,J=0.84Hz,1H)。质量(ES+):727.26(M+Na)+ |
IB.108 | 1.06(d,J=7.15Hz,3H),1.19(s,3H),1.25-1.41(m,1H),1.55(s,3H),1.74-1.97(m,3H), 2.29-2.50(m,4H),2.81(s,1H),3.43(m,3H),3.68(d,J=17.09Hz,1H),3.75(d,J=16.15Hz, 1H),3.77(s,3H),4.46(d,J=8.71Hz,1H),4.62(d,J=15.45Hz,1H),4.80(d,J=15.32Hz,1H), |
5.33-5.50(m,1H),6.41(dd,J1=10.09Hz,J2=1.69Hz,1H),6.45(s,1H),6.51(dd,J1=3.43Hz, J2=1.69Hz,1H),7.13(d,J=3.39Hz,1H),7.18(d,J=10.15Hz,1H),7.59(d,J=0.88Hz,1H)。质 量(ES+):697.29(M+Na)+ | |
IB.109 | 1.06(d,J=7.15Hz,3H),1.21(s,3H),1.37-1.41(m,1H),1.44(s,3H),1.45(s,3H),1.56(s,3H), 1.77-1.97(m,3H),2.29-2.52(m,4H),3.05(d,J=2.12Hz,1H),3.42-3.47(m,3H), 2.71-3.75(m,5H),4.46(d,J=8.69Hz,1H),4.62(d,J=15.42Hz,1H),4.74(d,J=15.43Hz,1H), 5.33-5.50(m,1H),6.41(dd,J1=10.15Hz,J2=1.76Hz,1H),6.45(s,1H),6.50(dd,J1=3.48Hz, J2=1.64Hz,1H),7.13(d,J=3.41Hz,1H),7.18(dd,J1=10.12Hz,J2=0.95Hz,1H),7.59(d, J=0.88Hz,1H)。质量(ES+):725.30(M+Na)+ |
IB.110 | 1.06(d,J=7.15Hz,3H),1.18(s,1H),1.35-1.42(m,1H),1.15(s,3H),1.47(s,3H),1.55(s,3H), 1.59-1.98(m,3H),2.17-2.51(m,4H),3.88(m,1H),2.97(s,1H),3.39-3.45(m,1H),3.72(s, 2H),4.43-4.45(m,1H),4.64-4.81(m,2H),5.33-5.49(m,1H),6.39(dd,J1=10.16Hz,J2=1.75Hz, 1H),6.45(s,1H),6.50(dd,J1=3.45Hz,J2=1.76Hz,1H),7.13(d,J=3.44Hz,1H),7.17(dd, J1=10.12Hz,J2=0.76Hz,1H),7.58(d,J=0.90Hz,1H)。质量(ES+):683.10(M+Na)+ |
IB.111 | 1.06(d,J=7.13Hz,3H),1.23(s,3H),1.36-1.41(m,1H),1.56(d,J=21.29Hz,3H),1.62(d, J=21.37Hz,3H),1.77-1.99(m,3H),2.28-2.53(m,4H),2.95(s,1H),3.39-3.43(m,1H),3.67(d, J=16.95Hz,1H),3.74(d,J=16.49Hz,1H),4.44(d,J=8.03Hz,1H),4.60(d,J=15.23Hz,1H), 4.86(d,J=15.34Hz,1H),5.33-5.50(m,1H),6.39(dd,J1=10.11Hz,J2=1.63Hz,1H),6.45(s,1H), 6.50(dd,J1=3.35Hz,J2=1.50Hz,1H),7.12(d,J=3.42Hz,1H),7.19(d,J=10.13Hz,1H),7.58(s, 1H)。质量(ES+):685.10(M+Na)+ |
IB.112 | 1.06(d,J=7.15Hz,3H),1.17(s,3H),1.35-1.40(m,1H),1.55(s,3H),1.76-1.97(m,3H), 2.28-2.47(m,4H),2.71(s,1H),3.42-3.47(m,1H),3.69(d,J=16.76Hz,1H),3.78(d,J=16.97Hz, 1H),3.82(S,3H),4.44(d,J=8.22Hz,1H),4.69(d,J=15.50Hz,1H),4.82(d,J=15.54Hz,1H), 5.30-5.60(m,1H),6.23(d,J=11.91Hz,1H),6.33(d,J=12.06Hz,1H),6.40(dd,J1=10.14Hz, J2=1.58Hz,1H),6.45(s,1H),6.50(dd,J1=3.31Hz,J2=1.51Hz,1H),7.13(d,J=3.47Hz,1H), 7.19(d,J=10.14Hz,1H),7.59(s,1H)。质量(ES+):687.73 |
IB.113 | 1.06(d,J=7.12Hz,3H),1.16(s,3H),1.32(t,3H),1.35-1.42(m,2H),1.56(s,3H),1.72-1.97(m, 3H),2.28-2.48(m,4H),2.86(s,1H),3.42-3.45(m,1H),3.68(d,J=16.77Hz,1H),3.77(d, J=16.62Hz,1H),4.26(q,J=7.07Hz,2H),4.46(d,J=8.36Hz,1H),4.75(d,J=15.39Hz,1H), 4.80(d,J=15.39Hz,1H),5.30-5.49(m,1H),6.41(dd,J1=10.14Hz,J2=1.76Hz,1H), 6.46(s,1H),6.50(dd,J1=3.45Hz,J2=1.76Hz,1H),6.85(d,J=15.75Hz,1H),6.90(d,J=15.90Hz, 1H),7.13(d,J=3.74Hz,1H),7.20(dd,J1=10.19Hz,J2=0.84Hz,1H),7.59(d,J=0.87Hz,1H)。质 量(ES+):701.0 |
IB.114 | 0.96(d,J=6.72Hz,6H),1.06(d,J=7.13Hz,3H),1.17(s,3H),1.25-1.41(m,1H),1.56(s,3H), 1.74-2.00(m,4H),2.28-2.49(m,4H),2.86(s,1H),3.42-3.45(m,1H),3.68(d,J=16.76Hz,1H), 3.78(d,J=16.83Hz,1H),4.00(d,J=6.70Hz,2H),4.46(d,J=8.56Hz,1H),4.75(d,J=15.47Hz, 1H),4.80(d,J=15.38Hz,1H),5.30-5.49(m,1H),6.41(dd,J1=10.15Hz,J2=1.80Hz,1H), 6.46(s,1H),6.50(dd,J1=3.50Hz,J2=1.73Hz,1H),6.85(d,J=15.79Hz,1H),6.92(d,J=15.93Hz, 1H),7.13(d,J=3.32Hz,1H),7.20(dd,J1=10.12Hz,J2=0.96Hz,1H),7.59(d,J=0.90Hz,1H)。质 量(ES+):729.1 |
IB.115 | 0.95(t,J=7.37Hz,6H),1.06(d,J=7.10Hz,3H),1.17(s,3H),1.36-1.45(m,3H),1.56(s,3H), 1.67-1.97(m,7H),2.28-2.51(m,4H),2.82(s,1H),3.42-3.45(m,1H),3.72(d,J=16.78Hz,1H), 3.77(d,J=16.74Hz,1H),4.22(t,J=6.67Hz,2H),4.47(d,J=8.32Hz,1H),4.75(d,J=15.54Hz, 1H),4.79(d,J=15.52Hz,1H),5.33-5.49(m,1H),6.41(dd,J1=10.13Hz,J2=1.66Hz,1H), 6.46(s,1H),6.50(dd,J1=3.33Hz,J2=1.52Hz,1H),6.84(d,J=15.81Hz,1H),6.90(d,J=15.77Hz, 1H),7.13(d,J=3.40Hz,1H),7.20(d,J=10.18Hz,1H),7.59(s,1H)。质量(ES+):729.1 |
IB.116 | 1.06(d,J=7.16Hz,3H),1.18(d,J=7.07Hz,3H),1.19(d,J=6.98Hz,3H),1.23(s,3H), 1.31-1.36(m,1H),1.62(s,3H),1.75-2.04(m,4H),2.17-2.82(m,6H),3.19(s,1H), 3.41-3.45(m,1H),3.65-3.75(m,1H),4.53(d,J=15.43Hz,1H),4.63(s,1H),4.73(d, J=15.42Hz,1H),6.11(s,1H),6.38(dd,J1=10.04Hz,J2=1.72Hz,1H),6.49(dd,J1=3.43Hz, J2=1.62Hz,1H),7.18(d,J=3.35Hz,1H),7.24(d,J=10.57Hz,1H),7.58(d,J=0.75Hz,1H)。质 量(ES+):665.1(M+Na)+ |
IB.117 | 0.91(t,J=7.48Hz,3H),1.05(d,J=7.13Hz,3H),1.15(d,3H,J=7.02Hz),1.22(s,3H), 1.38-2.00(m,6H),1.56(s,3H),2.28-2.46(m,5H),3.19(d,1H,J=3.09Hz),3.45(m,1H), 3.68-3.73(m,2H),4.44-4.46(m,1H),4.51(d,J=15.29Hz,1H),4.75(d,J=15.38Hz,1H), 5.33-5.52(m,1H),6.40(dd,J1=10.18Hz,J2=1.78Hz,1H),6.45(s,1H),6.50(dd,J1=3.46Hz, |
J2=1.61Hz,1H),7.13(d,J=3.32Hz,1H),7.18(d,J1=10.03Hz,J2=0.94Hz,1H),7.58(d, J=0.89Hz,1H)。质量(ES+):659.1 | |
IB.118 | 1.05(d,J=7.15Hz,3H),1.20(s,3H),1.35-1.40(m,1H),1.59(s,3H),1.77-2.00(m,3H), 2.28-2.52(m,4H),3.12(d,J=2.71Hz,1H),3.41-3.45(m,1H),3.68(d,J=16.77Hz,1H),3.75(d J=16.87Hz,1H),4.48-4.50(m,1H),4.75-4.96(m,2H),5.33-5.50(m,1H),6.41(dd, J1=10.08Hz,J2=1.70Hz,1H),6.46(s,1H),6.49(dd,J1=3.44Hz,J2=1.76Hz,1H),6.55(dd, J1=3.51Hz,J2=1.65Hz,1H),7.11(d,J=3.34Hz,1H),7.22-7.25(m,2H),7.57(d,J=0.83Hz,1H), 7.61(d,J=0.85Hz,1H)。质量(ES+):669.1 |
IB.119 | 1.06(d,J=7.12Hz,3H),1.17(s,3H),1.30(d,J=6.20Hz,6H),1.36-1.41(m,1H),1.56(s,3H), 1.72-1.97(m,3H),2.28-2.50(m,4H),2.82(s,1H),3.42-3.45(m,1H),3.67(d,J=16.71Hz,1H), 3.76(d,J=16.51Hz,1H),4.46(d,J=8.56Hz,1H),4.74(d,J=15.47Hz,1H),4.79(d,J=15.41Hz, 1H),5.08-5.13(m,1H),5.33-5.49(m,1H),6.41(dd,J1=10.16Hz,J2=1.58Hz,1H),6.46(s,1H), 6.50(dd,J1=3.36Hz,J2=1.62Hz,1H),6.83(d,J=15.87Hz,1H),6.88(d,J=15.76Hz,1H), 7.13(d,J=3.39Hz,1H),7.20(d,J=10.29Hz,1H),7.58(s,1H)。质量(ES+):715.1 |
化合物 编号 | 1H-NMR(δppm),质量(EI/ES+,m/z) |
IB.120 | 1.03(d,3H,J=7.05Hz),1.15(s,3H),1.16(s,6H),1.33-1.39(m,1H),1.55(s,1H),1.67-2.00(m, 3H),2.29-2.59(m,4H),3.39-3.49(m,1H),3.51(d,1H,J=4.81Hz),3.54(d,1H,J=11.65Hz), 3.71(d,1H,J=16.53Hz),3.77(d,1H,J=16.53Hz),4.73(t,1H,J=5.86Hz),4.33-4.35(m,1H) 4.64(d,1H,J=15.64Hz),4.68(d,1H,J=15.66Hz),5.07(s,1H),5.37-5.53(m,1H),6.31-6.33(m, 1H),6.33(s,1H),6.54(dd,1H,J1=3.41Hz,J2=1.58Hz),7.12(d,1H,J=3.37Hz),7.26(d,1H, J=10.30Hz),7.66(s,1H)。质量(ES+):697.07(M+Na)+ |
IB.121 | 1.05(d,3H,J=7.11Hz),1.18(s,3H),1.35-1.40(m,1H),1.56(s,1H),1.73-2.00(m,3H), 2.28-2.55(m,4H),3.01(d,1H,J=2.36Hz),3.42-3.46(m,1H),3.66(d,1H,J=16.75Hz),3.77(d 1H,J=16.77Hz),4.46(d,1H,J=8.20Hz),4.67(d,1H,J=15.43Hz),4.78(d,1H,J=15.43Hz), 5.33-5.49(m,1H),5.92(d,1H,J=10.35Hz),6.12(dd,1H,J1=17.32Hz,J2=10.52Hz), 6.39-6.46(m,1H),6.43(d,1H,J=13.3Hz),6.50(dd,1H,J1=3.27Hz,J2=1.52Hz),7.12(d,1H, J=3.39Hz),7.19(d,1H,J=10.12Hz),7.58(s,1H)。质量(ES+):629.05 |
IB.122 | 0.86(t,J=6.57Hz,6H),1.06(d,J=7.13Hz,3H),1.16(s,3H),1.27-1.41(m,1H),1.55(s,3H) 1.61-1.98(m,8H),2.29-2.51(m,4H),3.38-3.42(m,1H),3.64-3.79(m,3H),4.36(d,J=6.47Hz, 1H),4.68-4.82(m,3H),5.35-5.51(m,1H),6.35(dd,J1=10.15Hz,J2=1.67Hz,1H),6.38(s, 1H),6.52(dd,J1=3.40Hz,J2=1.68Hz,1H),7.12(d,J=3.46Hz,1H),7.27(d,J=9.97Hz,1H), 7.62(s,1H)。质量(ES+):689.1 |
IB.123 | 0.30-0.34(m,2H),0.60-0.64(m,2H),1.06(d,J=7.15Hz,3H),1.19(s,3H),1.36-1.41(m,1H), 1.55(s,3H),1.64-1.99(m,4H),2.29-2.51(m,4H),2.61(s,1H),3.42-3.47(m,1H),3.69(d J=16.73Hz,1H),3.77(d,J=16.72Hz,1H),3.99(d,J=7.39Hz,2H),4.44(d,J=8.47Hz,1H) 4.65-4.74(m,2H),5.33-5.49(m,1H),6.41(dd,J1=10.13Hz,J2=1.66Hz,1H),6.46(s,1H), 6.51(dd,J1=3.43Hz,J2=1.68Hz,1H),7.13-7.17(m,2H),7.59(s,1H)。质量(ES+):673.0 |
IB.124 | 1.05(d,J=7.07Hz,3H),1.15(s,3H),1.29-1.41(m,1H),1.54(s,3H),1.72-2.00(m,3H), 2.28-2.50(m,4H),2.76(s,3H),3.39-3.43(m,1H),3.73(d,J=16.53Hz,1H),3.79(d,J=16.54Hz, 1H),4.16(m,2H),4.36(d,J=6.03Hz,1H),4.93(s,1H),5.35-5.51(m,1H),6.35(d,J=10.19Hz, 1H),6.37(s,1H),6.52(dd,J1=3.09Hz,J2=1.32Hz,1H),7.12(d,J=3.40Hz,1H),7.27(d, J=10.15Hz,1H),7.62(s,1H)。质量(ES+):707.1(M+Na)+ |
IB.125 | 1.06(d,J=7.13Hz,3H),1.20-1.42(m,8H),1.55(s,3H),1.71-2.00(m,7H),2.28-2.49(m,4H), 2.66(s,1H),3.43-3.47(m,1H),3.69(d,J=17.44Hz,1H),3.76(d,J=16.97Hz,1H),4.44(d, J=8.32Hz,1H),4.63(d,J=15.47Hz,1H),4.70(d,J=15.45Hz,1H),5.05-5.09(m,1`H), 5.33-5.49(m,1H),6.40(dd,J1=10.14Hz,J2=1.48Hz,1H),6.46(s,1H),6.51(dd,J1=3.32Hz, J2=1.53Hz,1H),7.13-7.16(m,2H),7.59(s,1H)。质量(ES+):687.1 |
IB.126 | 1.06(d,J=7.07Hz,3H),1.20-1.99(m,15H),2.20-2.49(m,5H),2.60(s,1H),3.44(m,1H), 3.69(d,J=16.73Hz,1H),3.77(d,J=16.67Hz,1H),4.04(d,J=7.15Hz,2H),4.44(d,J=7.91Hz, 1H),4.64-4.73(m,2H),5.33-5.49(m,1H),6.40(d,J=10.02Hz,1H),6.46(s,1H),6.50(m,1H), 7.13-7.17(m,2H),7.59(s,1H)。质量(ES+):701.1 |
IB.127 | 1.06(d,J=7.16Hz,3H),1.17(d,J=2.39Hz,3H),1.18(d,J=2.37Hz,3H),1.21(s,3H), 1.35-1.41(m,1H),1.56(s,3H),1.77-2.00(m,3H),2.29-2.62(m,5H),3.21(d,J=2.62Hz,1H), 3.42-3.49(m,1H),3.67(d,J=16.86Hz,1H),3.75(d,J=16.81Hz,1H),4.45(d,J=8.59Hz,1H), |
4.52(d,J=15.45Hz,1H),4.74(d,J=15.33Hz,1H),5.33-5.50(m,1H),6.40(dd,J1=10.05Hz, J2=1.65Hz,1H),6.45(s,1H),6.50(dd,J1=3.50Hz,J2=1.69Hz,1H),7.13(dd,J1=3.56Hz, J2=0.57Hz,1H),7.19(dd,J1=0.75Hz,J2=0.22Hz,1H),7.58(s,1H)。质量(ES+):673.1 | |
IB.128 | 1.06(d,J=7.12Hz,3H),1.18(s,3H),1.35(s,3H),1.38-1.41(m,1H),1.43(s,3H),1.55(s,3H), 1.80-1.97(m,3H),2.40-2.64(m,5H),3.39-3.50(m,1H),3.71-3.83(m,3H),4.07-4.33(m,4H), 4.44(d,J=8.59Hz,1H),4.69-4.72(m,2H),5.31-5.51(m,1H),6.40(dd,J1=10.17Hz, J2=1.73Hz,1H),6.45(s,1H),6.50(dd,J1=3.47Hz,J2=1.64Hz,1H),7.13(d,J=3.43Hz,1H), 7.16(d,J=10.04Hz,1H),7.59(s,1H)。质量(ES+):733.0 |
IB.129 | 1.05(d,J=7.13Hz,3H),1.12-1.14(m,6H),1.24(s,3H),1.35-1.39(m,1H),1.56(s,3H), 1.80-2.11(m,3H),2.30-2.42(m,4H),3.19-3.35(m,4H),3.43-3.52(m,1H),3.60-3.82(m,2H), 4.12(d,J=3.12Hz,1H),4.42(d,J=8.25Hz,1H),4.48(d,J=15.61Hz,1H),4.76(d,J=15.96Hz, 1H),5.32-5.52(m,1H),6.39(dd,J1=10.12Hz,J2=1.75Hz,1H),6.45(s,1H),6.50(dd, J1=3.47Hz,J2=1.67Hz,1H),7.14(d,J=3.39Hz,1H),7.16(dd,J1=10.13Hz,J2=0.97Hz,1H), 7.58(d,J=0.78Hz,1H)。质量(ES+):674.1 |
IB.130 | 1.05(d,J=7.17Hz,3H),1.22(s,3H),1.34-1.40(m,1H),1.56(s,3H),1.56-1.60(m,6H), 1.77-2.07(m,3H),2.28-2.42(m,4H),3.40-3.49(m,5H),3.62-3.82(m,2H),3.86(d,J=3.2.5Hz, 1H),3.42(d,J=8.41Hz,1H),4.52(d,J=15.61Hz,1H),4.74(d,J=15.58Hz,1H),5.32-5.51(m, 1H),6.39(dd,J1=10.11Hz,J2=1.68Hz,1H),6.45(s,1H),6.50(dd,J1=3.41Hz,J2=1.58Hz,1H) 7.13(d,J=3.41Hz,1H),7.18(d,J=10.00Hz,1H),7.59(d,J=0.74Hz,1H)。质量(ES+)=686.1 |
IB.131 | 1.05(d,J=7.11Hz,3H),1.20(s,3H),1.34-1.40(m,1H),1.55(s,3H),1.77-2.04(m,3H),2.30(s, 3H),2.39-2.53(m,8H),3.48(m,5H),3.64(d,J=15.98Hz,1H),3.66(s,1H),3.77(d,J=17.39Hz, 1H),4.42(d,J=8.06Hz,1H),4.57(d,J=15.59Hz,1H),4.73(d,J=15.61Hz,1H),5.32-5.49(m, 1H),6.39(dd,J1=10.15Hz,J2=1.22Hz,1H),6.45(s,1H),6.50(dd,J1=3.11Hz,J2=1.26Hz,1H) 7.14(d,J=3.49Hz,1H),7.17(d,J=10.13Hz,1H),7.59(s,1H)。质量(ES+):701.1 |
IB.132 | 1.12(s,3H),1.29-1.34(m,1H),1.48(d,J=7.34Hz,3H),1.55(s,3H),1.74-2.16(m,4H), 2.33-2.81(m,4H),3.35(t,d,J1=16.65Hz,J2=2.31Hz,1H),3.82(t,d,J1=16.66Hz,J2=1.98Hz, 1H),4.26(m,2H),4.46(d,J=8.42,1H),5.32-5.49(m,1H),6.39(dd,J1=10.13Hz,J2=1.75Hz, 1H),6.44(s,1H),6.51(dd,J1=3.50Hz,J2=1.65Hz 1H),7.17-7.19(m,1H),7.61(s,1H)。质量 (ES+):575.1 |
IB.133 | 1.14(s,3H),1.19(d,J=6.97Hz,3H),1.25-1.32(m,1H),1.48(d,J=7.33Hz,3H),1.58(s,3H) 1.75-2.15(m,4H),2.33-2.62(m,5H),3.20(dd,J1=17.13Hz,J2=0.74Hz,1H),3.84-3.90(m,2H), 4.40(m,2H),4.72(dd,J1=15.25Hz,J2=1.33Hz,1H),5.33-5.51(m,1H),6.40(dd,J1=10.13Hz, J2=1.69Hz,1H),6.44(s,1H),6.51(dd,J1=3.43Hz,J2=1.57Hz,1H),7.18-7.20(m,2H), 7.61(d,J=0.73Hz,1H)。质量(ES+):645.0 |
IB.134 | 1.06(d,J=7.16Hz,3H),1.17(d,J=2.39Hz,3H),1.18(d,J=2.37Hz,3H),1.21(s,3H), 1.35-1.41(m,1H),1.56(s,3H),1.77-2.00(m,3H),2.29-2.62(m,5H),3.21(d,J=2.62Hz,1H), 3.42-3.49(m,1H),3.67(d,J=16.86Hz,1H),3.75(d,J=16.81Hz,1H),4.45(d,J=8.59Hz,1H), 4.52(d,J=15.45Hz,1H),4.74(d,J=15.33Hz,1H),5.33-5.50(m,1H),6.40(dd,J1=10.05Hz, J2=1.65Hz,1H),6.45(s,1H),6.50(dd,J1=3.50Hz,J2=1.69Hz,1H),7.13(dd,J1=3.56Hz, J2=0.57Hz,1H),7.19(dd,J1=0.75Hz,J2=0.22Hz,1H),7.58(s,1H)。质量(ES+):675.0 |
IB.135 | 1.06(d,J=7.12Hz,3H),1.19(s,3H),1.36-1.41(m,1H),1.55(s,3H),1.77-1.97(m,3H),2.32(s, 3H),2.29-2.49(m,5H),3.41-3.58(m,1H),3.73-3.75(m,2H),4.45(d,J=8.67Hz,1H),4.77(d, J=15.28Hz,1H),4.98(d,J=15.27Hz,1H),5.31-5.50(m,1H),6.40(dd,J1=10.15Hz, J2=1.65Hz,1H),6.45(s,1H),6.50(dd,J1=3.39Hz,J2=1.64Hz,1H),7.12(d,J=3.45Hz,1H), 7.15(dd,J=9.90Hz,1H),7.59(s,1H)。质量(ES+):699.0 |
IB.136 | 1.05(t,J=7.09Hz,6H),1.05(d,J=6.67Hz,3H),1.34-1.40(m,1H),1.55(s,3H),1.76-2.02(m, 3H),2.28-2.62(m,4H),2.56(q,J=7.22Hz,2H),3.26-3.39(m,3H),3.44-3.47(m,1H),3.63(d, J=16.46Hz,1H),3.85(d,J=16.45Hz,1H),4.42(d,J=8.63Hz,1H),5.30-5.81(m,1H),6.39(dd, J1=10.17Hz,J2=1.45Hz,1H),6.45(s,1H),6.50(dd,J1=3.30Hz,J2=1.61Hz,1H),7.14(d, J=3.21Hz,1H),7.15(d,J=9.85Hz,1H),7.59(s,1H)。质量(ES+):630.1 |
化合物 编号 | 1H-NMR(δppm),质量(EI/ES+,m/z) |
IB.137 | 1.06(d,J=7.13Hz,3H),1.20(s,3H),1.32(d,J=6.25Hz,3H),1.32(d,J=6.13Hz,3H), 1.35-1.39(m,1H),1.55(s,3H),1.71-1.99(m,3H),2.28-2.49(m,4H),2.53(s,1H),3.42-3.46(m, 1H),3.69(d,J=16.80Hz,1H),3.76(d,J=16.64Hz,1H),4.44(d,J=8.28Hz,1H),4.64(d, |
J=15.56Hz,1H),4.70(d,J=15.45Hz,1H),4.82-4.90(m,1`H),5.33-5.49(m,1H),6.41(dd, J1=10.17Hz,J2=1.38Hz,1H),6.46(s,1H),6.50(dd,J1=3.26Hz,J2=1.44Hz,1H),7.13-7.16(m, 2H),7.59(s,1H)。质量(ES+):661.1 | |
IB.138 | 1.06(d,J=7.13Hz,3H),1.20(s,3H),1.35-1.41(m,1H),1.55(s,3H),1.72(s,1H),1.76(s,3H), 1.74-1.98(m,3H),2.28-2.53(m,5H),3.42-3.46(m,1H),3.69(d,J=16.85Hz,1H),3.76(d, J=16.94Hz,1H),4.43(d,J=8.85Hz,1H),4.64-4.68(m,3H),5.33-5.49(m,1H),6.39(dd, J1=10.11Hz,J2=1.71Hz,1H),6.46(s,1H),6.50(dd,J1=3.45Hz,J2=1.71Hz,1H),7.13-7.16(m,, 2H),7.59(d,J=0.83Hz,1H)。质量(ES+):687.1 |
IB.139 | 0.87(t,J=6.15Hz,3H),1.06(d,J=7.15Hz,3H),1.19(s,3H),1.28-1.40(m,1H),1.55(s,3H), 1.64-1.99(m,5H),2.28-2.59(m,5H),3.43-3.46(m,1H),3.69(d,J=16.84Hz,1H),3.76(d, J=16.70Hz,1H),4.14(t,J=6.75Hz,1H),4.44(d,J=8.29Hz,1H),4.65(d,J=15.47Hz,1H), 4.65(d,J=15.48Hz,1H),5.32-5.49(m,1H),6.40(dd,J1=10.13Hz,J2=1.66Hz,1H),6.46(s,1H), 6.50(dd,J1=3.42Hz,J2=1.70Hz,1H),7.13-7.16(m,,2H),7.59(s,1H)。质量(ES+):703.1 |
IB.140 | 0.94-1.02(m,2H),1.06(d,J=7.14Hz,3H),1.19(s,3H),1.23-1.41(m,3H),1.55(s,3H), 1.66-1.99(m,9H),2.29-2.49(m,4H),2.58(d,J=2.05Hz,1H),3.43-3.46(m,1H),3.68(d, J=16.65Hz,1H),3.77(d,J=16.93Hz,1H),3.97(d,J=6.45Hz,2H),4.44(d,J=8.23Hz,1H), 4.65(d,J=15.56Hz,1H),4.71(d,J=15.48Hz,1H),5.33-5.49(m,1H),6.40(dd,J1=10.16Hz, J2=1.50Hz,1H),6.46(s,1H),6.51(dd,J1=3.33Hz,J2=1.61Hz,1H),7.13-7.16(m,,2H),7.59(s, 1H)。质量(ES+):715.2 |
IB.141 | 1.06(d,J=7.13Hz,3H),1.20(s,3H),1.25-1.52(m,7H),1.55(s,3H),1.73-1.99(m,7H), 2.29-2.53(m,4H),2.63(s,1H),3.43-3.47(m,1H),3.68(d,J=16.79Hz,1H),3.77(d,J=16.71Hz, 1H),4.44(d,J=8.52Hz,1H),4.56-4.62(m,1H),4.64(d,J=15.48Hz,1H),4.70(d,J=15.53Hz, 1H),5.33-5.50(m,1H),6.40(dd,J1=10.11Hz,J2=1.71Hz,1H),6.46(s,1H),6.50(dd, J1=3.45Hz,J2=1.58Hz,1H),7.13-7.16(m,,2H),7.59(d,J=0.9Hz,1H)。质量(ES+):701.1 |
IB.142 | 0.88(m,9H),0.94-1.25(m,14H),1.38-1.41(m,1H),1.49-1.72(m,6H),1.78-1.99(m,3H), 2.28-2.55(m,5H),3.43-3.46(m,1H),3.68(d,J=17.42Hz,1H),3.76(d,J=16.72Hz,1H), 4.17(m,2H),4.44(d,J=7.54Hz,1H),4.64(d,J=15.74Hz,1H),4.76(d,J=15.62Hz,1H), 5.33-5.49(m,1H),6.40(d,J=10.10Hz,1H),6.46(s,1H),6.50(m,1H),7.13-7.16(m,,2H), 7.59(m,1H)。质量(ES+):745.1 |
IB.143 | 0.96(s,9H),1.06(d,J=7.05Hz,3H),1.19(s,3H),1.25-1.40(m,7H),1.55(s,3H),1.74-1.99(m, 3H),2.30-2.56(m,5H),3.44(m,1H),3.68(d,J=16.89Hz,1H),3.79(d,J=17.24Hz,1H),3.85(s, 2H),4.45(d,J=7.73Hz,1H),4.67(d,J=15.98Hz,1H),4.71(d,J=15.98Hz,1H),5.33-5.49(m, 1H),6.40(d,J=10.09Hz,1H),6.46(s,1H),6.50-6.51(m,1H),7.13-7.16(m,2H),7.59(s,1H)。 质量(ES+):689.1 |
IB.144 | 1.06(d,J=7.16Hz,3H),1.19(s,3H),1.25-1.39(m,1H),1.55(s,3H),1.76-2.10(m,9H), 2.28-2.67(m,6H),3.43-3.47(m,1H),33.67-3.79(m,2H),4.12(d,J=8.32Hz,1H),4.65-4.75(m, 2H),5.33-5.50(m,1H),6.40(dd,J1=10.11Hz,J2=1.64Hz,1H),6.46(s,1H),6.51(dd, J1=3.45Hz,J2=1.60Hz,1H),7.13-7.17(m,,2H),7.59(m,1H)。质量(ES+):687.1 |
IB.145 | 1.06(d,J=7.07Hz,3H),1.19(s,3H),1.36-1.41(m,1H),1.54(s,3H),1.70-1.94(m,3H), 2.17-2.49(m,5H),3.44(m,1H),3.68(d,J=16.70Hz,1H),3.76(d,J=16.66Hz,1H),4.42(d, J=7.94Hz,1H),4.70(s,2H),5.13(s,2H),5.32-5.49(m,1H),6.38-6.50(m,5H),7.12-7.14(m, 2H),7.43(s,1H),7.59(s,1H)。质量(ES+):699.1 |
IB.146 | 0.94(t,J=7.29Hz,3H),1.06(d,J=7.15Hz,3H),1.19(s,3H),1.25-1.43(m,3H),1.55(s,3H), 1.61-1.99(m,5H),2.28-2.49(m,4H),2.59(s,1H),3.44-3.47(m,1H),3.68-.379(m,2H),4.15(t, J=6.69Hz,1H),4.44(d,J=8.63Hz,1H),4.65(d,J=15.51Hz,1H),4.71(d,J=15.47Hz,1H), 5.33-5.49(m,1H),6.40(dd,J1=10.14Hz,J2=1.59Hz,1H),6.46(s,1H),6.50(dd,J1=3.39Hz, J2=1.60Hz,1H),7.13-7.17(m,2H),7.59(s,1H)。质量(ES+):675.1 |
IB.147 | 0.90(t,J=6.86Hz,3H),1.06(d,J=7.11Hz,3H),1.19(s,3H),1.33-1.43(m,5H),1.55(s,3H), 1.65-1.99(m,5H),2.28-2.53(m,4H),2.60(s,1H),3.42-3.47(m,1H),3.69(d,J=16.86Hz,1H), 3.76(d,J=16.62Hz,1H),4.15(t,J=6.78Hz,2H),4.44(d,J=8.38Hz,1H),4.66(d,J=15.54Hz, 1H),4.71(d,J=15.39Hz,1H),5.33-5.49(m,1H),6.40(dd,J1=10.08Hz,J2=1.55Hz,1H),6.46(s, 1H),6.50(dd,J1=3.36Hz,J2=1.74Hz,1H),7.13-7.17(m,2H),7.59(s,1H)。质量(ES+):689.2 |
IB.148 | 1.06(d,J=7.17Hz,3H),1.20(s,3H),1.24-1.25(m,6H),1.35-1.41(m,1H),1.56(s,3H), 1.77-1.98(m,3H),2.28-2.52(m,4H),2.82(s,1H),3.42-3.46(m,1H),3.67(d,J=16.93Hz,1H), 3.75(d,J=16.87Hz,1H),4.33(dd,J1=13.35Hz,J2=8.87Hz,1H),4.45(dd,J1=13.22Hz, J2=8.77Hz,1H),4.42-4.48(m,1H),4.58(d,J=15.35Hz,1H),4.78(d,J=15.36Hz,1H), |
5.31-5.49(m,1H),6.40(dd,J1=10.12Hz,J2=1.68Hz,1H),6.45(s,1H),6.50(dd,J1=3.43Hz, J2=1.64Hz,1H),7.12(d,J=3.44Hz,1H),7.17(dd,J=10.21Hz,1H),7.58(d,J=0.71Hz,1H)。质 量(ES+):677.1 | |
IB.149 | 1.06(d,J=7.10Hz,3H),1.18(s,3H),1.36(s,3H),1.38-1.43(m,1H),1.43(s,3H),1.55(s,3H), 1.77-1.98(m,3H),2.28-2.55(m,5H),3.43-3.46(m,1H),3.66-3.83(m,3H),4.07-4.36(m,4H), 4.44(d,J=7.86Hz,1H),4.67-(d,J=15.48Hz,1H),4.73(d,J=15.48Hz,1H),5.32-5.49(m,1H), 6.39(d,J=10.08Hz,1H),6.45(s,1H),6.50(d,J=1.59Hz,1H),7.13(d,J=3.39Hz,1H),7.15(d, J=10.24Hz,1H),7.59(s,1H)。质量(ES+):733.1 |
IB.150 | 1.06(d,J=7.08Hz,3H),1.18(s,3H),1.35(s,3H),1.38-1.43(m,1H),1.43(s,3H),1.55(s,3H), 1.77-1.97(m,3H),2.28-2.49(m,5H),3.42-3.46(m,1H),3.69(d,J=16.77Hz,1H),3.77(d, J=15.45Hz,1H),3.80(d,J=5.40Hz,1H),3.82(d,J=5.56Hz,1H),4.08(d,J=6.42Hz,1H), 4.10(d,J=6.85Hz,1H),4.18(d,J=5.35Hz,2H),4.32(m,1H),4.45(d,J=7.55Hz,2H),4.70(m, 1H),5.31-5.51(m,1H),6.39(d,J=10.13Hz,1H),6.45(s,1H),6.50(dd,J1=3.47Hz,J2=1.52Hz, 1H),7.12(d,J=3.44Hz,1H),7.14(d,J=10.15Hz,1H),7.59(s,1H)。质量(ES+):733.1 |
IB.151 | 1.05(d,J=7.11Hz,3H),1.20(s,3H),1.35-1.40(m,1H),1.54(s,3H),1.77-2.03(m,3H), 2.28-2.52(m,4H),3.39(d,J=72.79Hz,1H),3.39-3.46(m,5H),3.67-3.80(m,6H),4.42(d, J=8.10Hz,1H),4.59(d,J=15.59Hz,1H),4.74(d,J=15.59Hz,1H),5.32-5.49(m,1H),6.39(dd, J1=10.16Hz,J2=1.48Hz,1H),6.45(s,1H),6.50(dd,J1=3.26Hz,J2=1.59Hz,1H),7.14(d, J=2.57Hz,1H),7.16(d,J=10.25Hz,1H),7.59(s,1H)。质量(ES+):688.1 |
IB.152 | 1.05(d,J=7.10Hz,3H),1.20(s,3H),1.34(s,3H),1.34-1.40(m,1H),1.43(s,3H),1.55(s,3H), 1.77-2.03(m,3H),2.28-2.53(m,4H),3.23-3.30(m,1H),3.37-3.45(m,3H),3.63-3.79(m,3H), 4.02-4.24(m,2H),4.43(d,J=7.99Hz,1H),4.53(d,J=15.80Hz,1H),4.70(d,J=15.61Hz,1H), 5.15(s,1H),5.33-5.49(m,1H),6.39(dd,J1=10.16Hz,J2=1.42Hz,1H),6.45(s,1H),6.50(d, J1=3.31Hz,J2=1.54Hz,1H),7.14(d,J=3.39Hz,1H),7.18(d,J=9.90Hz,1H),7.59(s,1H)。质量 (ES+):732.1 |
化合物 编号 | 1H-NMR(δppm),质量(EI/ES+,m/z) |
IB.153 | 1.06(d,J=7.12Hz,3H),1.09(m,2H),1.20(s,3H),1.36-1.41(m,1H),1.51-1.99(m,15H), 2.29-2.49(m,4H),2.64(d,J=1.80Hz,1H),3.43-3.47(m,1H),3.69(d,J=16.81Hz,1H),3.76(d J=16.88Hz,1H),4.17(t,J=6.97Hz,2H),4.44(d,J=8.65Hz,1H),4.65(d,J=15.48Hz,1H), 4.71(d,J=15.44Hz,1H),5.33-5.49(m,1H),6.40(dd,J1=10.13Hz,J2=1.56Hz,1H),6.46(s,1H), 6.51(dd,J1=3.37Hz,J2=1.53Hz,1H),7.13-7.17(m,2H),7.59(d,J=0.70Hz,1H)。质量(ES+): 715.1 |
IB.154 | 0.93(d,J=6.53Hz,6H),1.06(d,J=7.11Hz,3H),1.20(m,2H),1.35-1.41(m,1H),1.55(s,3H), 1.57-1.66(m,2H),1.66-1.99(m,4H),2.29-2.49(m,4H),2.57(s,1H),3.43-3.46(m,1H),3.69(d, J=16.54Hz,1H),3.77(d,J=16.68Hz,1H),4.19(t,J=6.87Hz,2H),4.44(d,J=8.08Hz,1H), 4.65(d,J=15.53Hz,1H),4.71(d,J=15.51Hz,1H),5.33-5.49(m,1H),6.40(d,J=10.11Hz,1H) 6.46(s,1H),6.50(dd,J1=3.10Hz,J2=1.63Hz,1H),7.13-7.17(m,2H),7.59(s,1H)。质量(ES+): 689.1 |
IB.155 | 1.06(d,J=7.08Hz,3H),1.17(s,3H),1.36-1.40(m,1H),1.55(s,3H),1.74-2.11(m,5H), 2.29-2.63(m,6H),3.44(m,1H),3.67(d,J=16.71Hz,1H),3.76(d,J=16.62Hz,1H),4.45(d, J=8.31Hz,1H),4.51(t,J=6.24Hz,2H),4.61(d,J=15.49Hz,1H),4.73(d,J=15.42Hz,1H), 4.40(d,J=11.18Hz,1H),5.33-5.50(m,1H),6.40(d,J=11.18Hz,1H),6.45(s,1H),6.50(m,1H), 7.13(d,J=3.30Hz,1H),7.17(d,J=10.24Hz,1H),7.59(s,1H)。质量(ES+):706.1 |
IB.156 | 1.05(d,J=7.06Hz,3H),1.19(s,3H),1.31(s,3H),1.33(s,3H),1.37-1.41(m,1H),1.44(s,3H), 1.50(s,3H),1.55(s,3H),1.77-2.00(m,3H),2.28-2.50(m,4H),2.68(s,1H),3.45(m,1H) 3.66(d,J=13.96Hz,1H),3.77(d,J=16.58Hz,1H),4.05(t,J=5.83Hz,1H),4.24-4.34(m,4H) 4.46(d,J=7.50Hz,1H),4.62(dd,J1=7.80Hz,J2=2.15Hz,1H),4.69(s,2H),5.33-5.49(m,1H), 5.52(d,J=4.93Hz,1H),6.38(d,J=10.13Hz,1H),6.45(s,1H),6.50(dd,J1=3.19Hz,J2=1.47Hz, 1H),7.13(d,J=3.18Hz,1H),7.18(d,J=10.10Hz,1H),7.59(s,1H)。质量(ES+):861.1 |
IB.157 | 1.06(d,J=7.08Hz,3H),1.17(s,3H),1.36-1.40(m,1H),1.55(s,3H),1.74-2.11(m,5H), 2.29-2.63(m,6H),3.44(m,1H),3.67(d,J=16.71Hz,1H),3.76(d,J=16.62Hz,1H),4.45(d, J=8.31Hz,1H),4.51(t,J=6.24Hz,2H),4.61(d,J=15.49Hz,1H),4.73(d,J=15.42Hz,1H), 4.40(d,J=11.18Hz,1H),5.33-5.50(m,1H),6.40(d,J=11.18Hz,1H),6.45(s,1H),6.50(m,1H), 7.13(d,J=3.30Hz,1H),7.17(d,J=10.24Hz,1H),7.59(s,1H)。质量(ES+):720.1 |
IB.158 | 1.06(d,J=7.14Hz,3H),1.16(s,3H),1.35-1.41(m,1H),1.55(s,3H),1.77-1.97(m,3H). 2.12-2.51(m,5H),3.36(s,3H),3.43-3.47(m,1H),3.71(d,J=16.48Hz,1H),3.83(d,J=16.48Hz, 1H),4.05(d,J=15.61Hz,1H),4.10(d,J=15.58Hz,1H),4.44(d,J=8.60Hz,1H), 5.34-5.47(m,1H),6.41(dd,J1=10.16Hz,J2=1.69Hz,1H),6.46(s,1H),6.51(dd,J1=3.44Hz, J2=1.75Hz,1H),7.13(d,J=3.40Hz,1H),7.15(d,J=10.20Hz,1H),7.59(d,J=0.86Hz,1H)。质量 (ES+):589.1 |
IB.159 | 1.06(d,J=7.16Hz,3H),1.16(s,3H),1.22(t,J=7.01Hz,3H),1.36-1.41(m,1H),1.54(s,3H), 1.71-2.00(m,3H),2.28-2.51(m,4H),3.42-3.46(m,1H),3.46-3.59(m,2H),3.70(d, J=16.51Hz,1H),3.83(d,J=16.49Hz,1H),4.07-4.17(m,2H),4.44(d,J=8.80Hz,1H), 5.32-5.49(m,1H),6.41(dd,J1=10.12Hz,J2=1.68Hz,1H),6.46(s,1H),6.51(dd,J1=3.43Hz, J2=1.63Hz,1H),7.13-7.16(m,2H),7.59(s,1H)。质量(ES+):603.1 |
IB.160 | 0.91(d,J=6.70Hz,6H),1.06(d,J=7.07Hz,3H),1.15(s,3H),1.25-1.41(m,1H),1.54(s,3H), 1.67-1.97(m,5H),2.28-2.53(m,4H),3.22-3.28(m,2H),3.42-3.46(m,1H),3.71(d, J=16.42Hz,1H),3.84(d,J=16.45Hz,1H),4.06-4.16(m,2H),4.44(d,J=7.72Hz,1H), 5.32-5.49(m,1H),6.39-6.41(m,1H),6.46(s,1H),6.51(dd,J1=3.19Hz,J2=1.44Hz,1H) 7.12-7.15(m,2H),7.59(s,1H)。 质量(ES+):631.1 |
IC.1 | 1.03(d,J=7.07Hz,3H),1.13(d,J=7.68Hz,3H),1.15(s,3H),1.20-1.89(m,8H),2.15-2.44(m, 6H),2.85-2.88(m,1H),4.30-4.33(m,1H),4.82(s,2H),5.30-5.47(m,1H),6.34(dd, J1=10.13Hz,J2=1.17Hz,2H)。6.38(s,1H),7.05(dd,J=8.67Hz,2H),7.21(d,J=10.17Hz,1H), 7.43-7.47(m,2H)。质量(ES+):615.5(M+Na+)。 |
IC.2 | 1.03(d,J=7.01Hz,3H),1.11-1.14(m,6H),1.32-1.89(m,8H),2.20-2.44(m,6H),2.80-2.84(m, 1H),4.40(d,J=8.11Hz,1H),4.78(d,J=11.17Hz,1H),4.4.81(d,J=11.19Hz,1H), 5.32-5.49(m,1H),6.37(d,J=10.14Hz,1H),7.10(d,J=10.15Hz,1H),7.29(d,J=8.19Hz, 1H),7.44(d,J=8.19Hz,1H)7.57(s,1H)。质量(ES+):665.4(M+Na)+. |
IC.3 | 1.03(d,J=7.09Hz,3H),1.12(t,J=7.50Hz,3H),1.16(s,3H),1.16-1.95(m,8H),2.20-2.40(m, 6H),2.78-2.84(m,1H),4.41(d,J=8.70Hz,1H),5.28-5.48(m,1H),5.39(d,d J1=50.31Hz, J2=2.66Hz,1H),5.51(d,d J1=49.30Hz,J2=2.61Hz,1H),6.37(dd J1=10.15Hz,J2=1.74Hz,1H), 6.43(s,1H),7.10(dd J1=10.12Hz,J2=1.11Hz,1H)。质量(ES+):517.2 |
IC.4 | 1.11(d,J=7.09Hz,3H),1.21(s,3H),1.24-1.97(m,8H),2.28-2.50(m,4H),2.86-2.90(m,1H), 4.45-4.47(m,1H),5.30-5.52(m,1H),5.41(d,d J1=53.67Hz,J2=2.34Hz 1H),5.56(d,d J1=52.24Hz,J2=2.33Hz,1H),6.39(d,d J1=10.13Hz,J2=1.77Hz 1H),6.45(s,1H),6.51(d,d J1=3.50Hz,J2=1.72Hz 1H),7.12-7.15(m,2H)7.60(d,J=0.88Hz,1H)。质量(ES+):555.2 |
IC.5 | 1.10(d,J=7.17Hz,3H),1.21(s,1H),1.25-1.38(m,2H),1.55(s,1H),1.85-1.99(m,3H), 2.16-2.59(m,4H),2.88-2.93(m,1H),4.83(d,J=10.67Hz,1H),4.83(d,J=10.69Hz,1H), 5.03-5.09(m,1H),6.31-6.35(m,2H),6.54(dd,J1=3.47Hz,J2=1.71Hz,1H),7.03-7.07(m, 2H),7.26(d,J=10.03Hz,1H),7.45-7.49(m,2H),7.65(d,J=0.82Hz,1H)。质量(ES+):631.2 |
IC.6 | 1.12(d,J=7.07Hz,3H),1.21(s,3H),1.26-1.48(m,1H),1.53(s,3H),1.59-1.96(m,4H), 2.28-2.52(m,4H),2.82-2.86-2.89(m,1H),4.44-4.46(m,1H),4.93(d,J=11.263Hz,1H), 5.03(d,J=11.24Hz,1H),5.32-5.48(m,1H),6.39(dd,J1=10.11Hz,J2=1.68Hz,1H),6.45(s, 1H),6.52(dd,J1=3.41Hz,J2=1.70Hz,1H),7.11(d,J=5.71Hz,1H),7.13(s,1H),7.58-7.64(m, 4H)。质量(ES+):681.3 |
IC.7 | 1.09(d,J=6.89Hz,3H),1.20(s,3H),1.25-1.50(m,1H),1.55(s,3H),1.60-2.03(m,4H), 2.16-2.52(m,4H),2.92-3.13(m,1H),4.32(m,1H),4.83(d,J=10.85Hz,1H),4.87(d, J=10.88Hz,1H),5.13-5.51(m,1H),6.30-6.33(m,2H),6.55(s,1H),7.13(s,1H),7.26(d, J=10.22Hz,1H),7.33-7.58(m,4H),7.58-7.77(m,1H)。质量(ES+):647.2 |
IC.8 | 0.99(d,J=7.09Hz,3H),1.09(t,J=7.52Hz,3H),1.12(s,3H),1.22-1.88(m,8H),2.13-2.55(m, 6H),2.82-2.86(m,1H),4.25-4.27(m,1H),4.89(s,2H),4.96-4.98(m,1H), 5.30-5.50(m,1H),6.26-6.29(m,2H),7.21(dd,J1=10.03Hz,J2=1.05Hz,1H),7.56(d, J=8.26Hz,2H),7.61(d,J=8.30Hz,2H)。质量(ES+):643.0 |
IC.9 | 1.05(d,J=7.09Hz,3H),1.18(s,1H),1.20-1.87(m,8H),2.19-2.56(m,4H),2.58-2.70(m,1H), 2.86-2.90(m,1H),4.30-4.32(m,1H),4.80(d,J=10.70Hz,1H),4.85(d,J=10.70Hz,1H), 4.92-4.94(m,1H),6.05(m,1H),6.25(dd,J1=10.13Hz,J2=1.77Hz,1H),6.51(dd,J1=3.45Hz, J2=1.70Hz,1H),7.00-7.02(m,2H),7.29(d,J=10.11Hz,1H),7.43-7.46(m,2H), 7.63(d,J=0.85Hz,1H)。质量(ES+):613.0 |
IC.10 | 1.00(d,J=7.06Hz,3H),1.07(t,J=7.54Hz,3H),1.15(s,3H),1.25-1.92(m,8H),2.16-2.44(m, |
6H),2.81-2.84(m,1H),4.41(d,J=8.51Hz,1H),5.10(d,J=16.55Hz,1H),5.21(d,J=16.64Hz, 1H),5.30-5.46(m,1H),6.38(dd,J1=10.13Hz,J2=1.69Hz,1H),7.14(d,J=10.13Hz,1H), 7.46(d,J=8.54Hz,2H),7.85(d,J=8.58Hz,2H)。质量(ES+):637.1 |
化合 物编 号 | 1H-NMR(δppm),质量(EI/ES+,m/z) |
IC.11 | 1.10(d,J=7.08Hz,3H),1.22(s,3H),1.25-1.94(m,8H),2.27-2.65(m,5H),2.80-2.92(m,1H), 4.45-4.56(m,1H),5.41(dd J1=52.28Hz,J2=2.31Hz,1H),5.56(dd J1=53.72Hz,J2=2.34Hz, 1H),6.15(s,1H),6.37(dd J1=10.13Hz,J2=1.82Hz,1H),6.50(dd J1=3.48Hz,J2=1.70Hz,1H), 7.12(d,J=3.40Hz,1H),7.21(d,J=10.12Hz,1H),7.59(d,J=0.86Hz 1H)。质量(ES+):537.1 |
IC.12 | 0.89(t,J=7.33Hz,3H),1.03(d,J=7.07Hz,3H),1.16(s,3H),1.25-1.91(m,12H),2.17-2.44(m, 6H),2.80-2.84(m,1H),4.1-4.33(m,1H),5.30-5.58(m,3H),6.38(dd,J1=10.13Hz,J2=1.69Hz, 1H)。6.43(s,1H),7.11(dd,J=10.12Hz,J2=0.981H)。质量(ES+):537.1 |
IC.13 | 1.02(d,J=7.08Hz,3H),1.12(t,J=7.70Hz,3H),1.15(s,3H),1.32-1.37(m,1H),1.52(s,3H), 1.68-1.92(m,4H),2.22-2.39(m,4H),2.76-2.81(m,1H),3.84(s,3H),4.40-4.42(m,1H), 5.29-5.47(m,1H),6.38(dd J1=10.12Hz,J2=1.79Hz,1H),6.43(s,1H),7.12(dd J1=10.14Hz, J2=1.32Hz,1H)。质量(ES+):499.0 |
IC.14 | 1.08(d,J=7.08Hz,3H),1.20(s,3H),1.29-1.40(m,1H),1.55(s,3H),1.59-2.00(m,4H), 2.27-2.51(m,4H),2.88-2.92(m,1H),3.85(s,3H),4.33-4.35(m,1H),4.95-4.97(m,1H), 5.34-5.51(m,3H),6.33(dd J1=10.10Hz,J2=1.85Hz,1H),6.36(s,1H),6.52(dd J1=3.49Hz, J2=1.72Hz,1H),7.11(dd J1=3.48Hz,J2=0.53Hz,1H),7.26(dd J1=10.05Hz,J2=0.96Hz,1H), 7.62-7.63m,1H)。质量(ES+):537.0 |
IC.15 | 1.04(d,J=7.09Hz,3H),1.11-1.15(m,6H),1.34-1.85(m,8H),2.20-2.39(m,6H), 2.80-2.90(m,1H),4.38(d,J=8.66Hz,1H),4.86(d,J=10.78Hz,1H),4.92(d,J=10.77Hz, 1H),5.27-5.49(m,1H),6.36(dd,J1=10.14Hz,J2=1.80Hz 1H),6.43(s,1H),7.09(dd, J1=10.13Hz,J2=1.20Hz,1H),7.35-7.45(m,5H)。质量(ES+):575.0 |
IC.16 | 1.08(d,J=7.08Hz,3H),1.20(s,3H),1.22-1.97(m,8H),2.26-2.54(m,4H),2.91-2.95(m,1H), 4.31(d,J=6.59Hz,1H),4.85(d,J=10.66Hz,1H),4.88(d,J=10.66Hz,1H),5.24-5.56(m,1H), 6.28-6.31(m,2H),6.56(dd,J1=3.39Hz,J2=1.64Hz 1H),7.31(d,J=3.45Hz,1H),7.18-7.46(m, 6H),7.72(s,1H)。质量(ES+):613.0 |
IC.17 | 0.99(d,J=7.07Hz,3H),1.09(t,J=7.51Hz,3H),1.14(s,3H),1.19-1.96(m,8H),2.09-2.47(m, 12H),2.77-2.81(m,1H),4.40(d,J=6.30Hz,1H),4.74(d,J=18.25Hz,1H),4.82(d,J=18.27Hz, 1H),5.30-5.46(m,1H),6.38(dd,J1=10.15Hz,J2=1.79Hz,1H),6.43(s,1H),6.84(s,2H), 7.12(d,J=9.89Hz,1H)。质量(ES+):645.3 |
IC.18 | 1.03(d,J=7.09Hz,3H),1.14(s,3H),1.13(t,J=7.54Hz,3H),1.25-1.89(m,8H),2.17-2.40(m, 6H),2.81-2.83(m,1H),4.38-4.41(m,1H),4.81(d,J=10.91Hz,1H),4.88(d,J=10.91Hz, 1H),5.25-5.50(m,1H),6.35(d,d J1=10.13Hz,J2=1.65Hz),6.43(s,1H),7.10(d,d J1=10.10Hz, J2=0.67Hz 1H),7.34(d,J=8.40Hz,2H),7.40(d,J=8.39Hz,2H)。质量(ES+):609.0 |
IC.19 | 1.10(d,J=7.04Hz,3H),1.21(s,3H),1.30-1.96(m,8H),2.29-2.54(m,4H),2.90-2.93(m,1H), 4.33-4.36(m,1H),4.82(d,J=11.11Hz,1H),4.87(d,J=11.10Hz,1H),4.95-4.98(m,1H), 5.36-5.51(m,1H),6.33(dd,J1=10.13Hz,J2=1.75Hz,1H),7.14(d,J=3.45Hz,1H),7.25(d, J=10.09Hz,1H),7.32(dd,J1=8.22Hz,J2=1.89Hz 1H),7.44-7.46(m,1H),7.64(s,1H)。 质量(ES+):680.9 |
IC.20 | 1.09(d,J=7.00Hz,3H),1.20(s,3H),1.30-2.02(m,8H),2.26-2.53(m,4H),2.91-2.95(m,1H), 4.32(d,J=6.99Hz,1H),4.97(d,J=11.64Hz,1H),5.03(d,J=11.59Hz,1H),5.37-5.54(m,1H), 6.31-6.32(m,2H),6.56(dd,J1=3.28Hz,J2=1.56Hz,1H),7.13(d,J=3.41Hz,1H),7.18-7.31(m, 2H),7.42(d,J=1.43Hz,1H),7.58(d,J=8.25Hz,1H),7.70(s,1H)。质量(ES+):681.5 |
IC.21 | 1.11(d,J=6.97Hz,3H),1.22(s,3H),1.25-1.96(m,8H),2.28-2.58(m,4H),2.90-3.95(m,1H), 4.36(m,1H),4.83-4.88(m,3H),5.30-5.55(m,1H),6.34(d,d J1=10.10Hz,J2=1.68Hz,1H), 6.38(m,1H),6.53(d,d J1=3.39Hz,J2=1.65Hz,1H),7.13(d,J=3.43Hz,1H),7.124-7.42(m,4H), 7.50(s,1H),7.63(s,1H)。质量(ES+):647.7 |
IC.22 | 1.09(d,J=7.04Hz,3H),1.20(s,3H),1.25-1.97(m,8H),2.03-2.57(m,4H),2.89-2.93(m,1H), 4.33(d,J=6.78Hz,1H),4.95(d,J=10.92Hz,1H),5.05(d,J=10.89Hz,1H),5.12(m,1H), 5.30-5.30(m,1H),6.30-6.33(m,2H),6.54(dd,J1=3.39Hz,J2=1.63Hz 1H),6.74-6.78(m, |
2H),7.11(d,J=3.36Hz,1H),7.26(d,J=10.07Hz,1H),7.66(s,1H)。质量(ES+):667.0 | |
IC.23 | 1.10(d,J=7.05Hz,3H),1.22(s,3H),1.36-1.42(m,1H),1.55(s,3H),1.72-2.00(m,4H), 2.29-2.52(m,4H),2.87-2.92(m,1H),4.32-4.35(m,1H),4.93(d,J=11.04Hz,1H),4.97(d, J=11.07Hz,1H),5.05-5.06(m,1H),5.30-5.52(m,1H),6.33(dd,J1=10.09Hz,J2=1.88Hz 1H), 6.35(s,1H),6.54(dd,J1=3.49Hz,J2=1.72Hz 1H),7.13(d,J=3.39Hz 1H),7.26(dd, J1=10.07Hz,J2=1.01Hz 1H),7.51-7.69(m,4H),7.74(s,1H)。质量(ES+):681.5 |
实施例30:药理学活性:(a)类固醇受体结合试验:
类固醇受体结合试验由MDS Pharma Services在它们的台北(台湾)药理学实验室进行。(i)糖皮质激素受体结合试验
利用放射性配体结合试验,评价测试化合物对糖皮质激素受体的活性。在25℃,在RPMI-1640,10nM HEPES,pH 7.2温育培养基中,在3nM和/或10nM浓度的测试化合物不存在或存在时,用[3H]地塞米松温育用糖皮质激素受体转染的人HeLa细胞2小时。通过离心将游离[3H]地塞米松从培养基中去除,并通过液体闪烁计数测定上清中受体结合配体的浓度。
作为每一试验的必需部分,同时测试作为对照化合物的地塞米松,以确保所得结果的有效性。利用测试单一浓度的化合物和相应的放射标记的配体评价抑制百分比。以特异性结合的抑制百分比表示结果。值为每一浓度的重复测定的平均值。表7:糖皮质激素受体结合(体外)筛选
化合物编号 | 糖皮质激素受体结合%抑制率 |
IA.143 | 58b |
IA.161 | 55b |
IA.157 | 56b |
IA.159 | 36b |
IA.168 | 40a |
IB.2 | 55a |
IB.4 | 88b |
IB.6 | 92b |
IB.7 | 82b |
IB.8 | 93b |
化合物编号 | 糖皮质激素受体结合 %抑制率 |
IB.10 | 82b |
IB.13 | 79b |
IB.14 | 85b |
IB.15 | 83b |
IB.50 | 74b |
IB.51 | 67b |
IB.54 | 82b |
IB.66 | 72b |
IB.67 | 77b |
IB.70 | 43a |
IB.73 | 45a |
IB.88 | 46a |
IB.100 | 45a |
IB.101 | 45a |
IB.103 | 78b |
IB.104 | 72b |
IB.105 | 42a |
IC.3 | 72c |
IC.4 | 73b |
IC.5 | 75c |
IC.7 | 41b |
丙酸氟替卡松 | 88b |
布德松 | 85b |
a3nM时的%抑制率;b10nM时的%抑制率;c100nM时的%抑制率(b)巴豆油耳水肿
将小鼠(雄性,CD-1)分成不同的组。将测试化合物溶解在吡啶-水-丙酮(4∶2∶14)溶液中,将10μl化合物或载体溶液施用于小鼠的左耳。各小鼠的右耳同时被施加10μl的吡啶∶水∶丙酮(4∶2∶14)溶液。在化合物或载体施用2小时之后,将10μl巴豆油溶液施用于所有动物的左耳。在巴豆油处理6hr之后,杀死动物;割下耳朵并分别称重。
表8:巴豆油耳水肿筛选
化合物编号 | 平均%抑制率 |
IA.3 | 45.31a |
IA.56 | 34.59a |
IA.184 | 49.06a |
IA.185 | 49.06a |
IB.20 | 61.49a |
IB.33 | 76.16a |
IB.34 | 64.39a |
IB.35 | 60.18a |
IB.37 | 57.12a |
IB.44 | 75.19a |
化合物编号 | 平均%抑制率 |
IB.46 | 75.97a |
IB.49 | 71.82a |
IB.52 | 78.12a |
IB.53 | 71.19a |
IB.55 | 74.78a |
IB.57 | 74.43a |
IB.64 | 72.75a |
IB.73 | 76.24a |
IB.77 | 71.71a |
IB.81 | 77.75a |
IB.98 | 73.71b |
IB.102 | 73.63b |
IB.112 | 66.94b |
IB.138 | 72.48b |
IB.150 | 77.76b |
IB.159 | 66.02b |
IC.13 | 41.79a |
IC.14 | 61.46a |
丙酸氟替卡松 | 81.09a |
地塞米松 | 50.05a |
a在1.6μg下的抑制率;b在0.5μg下的抑制率(c)棉球肉芽肿
利用棉球肉芽肿方法,使用SD大鼠来评价测试化合物的抗炎活性。制备重量为20mg的灭菌棉球。将测试化合物溶解在丙酮中,以便得到500μl的各棉球所需要的量。将不同的球浸渍500μl丙酮,以含有所需的测试化合物量,并使其干燥。用500μl丙酮浸渍载体对照球。将大鼠分成不同的组。将两个棉球手术植入各大鼠的肩胛区。在该植入的第六天时,将球连同肉芽肿取出。也将胸腺从各动物中分离并称重。将具有肉芽肿的球在60℃下干燥20小时并称重。计算干肉芽肿和胸腺的平均重量、体重增加/100g体重。
表9:棉球肉芽肿试验
化合物编号 | 剂量 (mcg) | 肉芽肿的平均 %抑制率 | 胸腺重量* (%减少) |
IA.137 | 1000 | 65.58 | 1.59 |
IA.138 | 1000 | 66.16 | 15.45 |
IA.140 | 1000 | 62.54 | -36.16 |
IA.141 | 1000 | 63.1 | -18.26 |
IA.142 | 10 | 45.36 | -8.43 |
IA.197 | 1000 | 79.04 | -8.89 |
IB.5 | 10 | 39.79 | -0.39 |
IB.7 | 1000 | 78.82 | 14.89 |
IB.16 | 3 1000 | 68.92 77.36 | -11.06 -11.65 |
IB.163 | 3 10 | 45.8 76.13 | -5.44 13.77 |
IC.6 | 1000 | 84.96 | 10.96 |
IC.8 | 3 | 45.15 | 3.38 |
IC.9 | 3 | 34.3 | 2.51 |
丙酸氟替卡松 | 1000 | 75.03 | 82.36 |
地塞米松 | 1000 | 44.73 | 68.66 |
*在所有化合物中(除参照化合物之外),当与载体对照相比时胸腺重量变化与体重增加在统计学上是不显著的。(d)在SD大鼠中交联葡聚糖(Sephadex)诱导的肺水肿
在无菌盐水中制备Sephadex G-200(10mg/ml),并使其在室温下膨胀至少三天。通过在冰冷盐水中研磨并声波处理固体,制备测试化合物为悬浮液。在轻 度醚麻醉下,在气管内施用交联葡聚糖(5mg/kg)之前的24小时以及2小时,气管内施用所有化合物。用载体代替交联葡聚糖施用于载体对照动物。在交联葡聚糖灌注之后24小时,从各个动物切下肺和胸腺并称重。针对100g原始体重校正肺和胸腺的湿重。计算由交联葡聚糖引起的肺重量的增加百分比以及化合物对其的抑制。也计算相比于载体对照组的胸腺的抑制百分比。
表10a:在SD大鼠中交联葡聚糖肺水肿模型中化合物的治疗指数
化合物编号 | ED50肺水肿 (mg/kg,i.t.) | ED50胸腺 (mg/kg,i.t.) | 治疗指数 ED50胸腺退化/ ED50肺水肿 |
IB.51 | 0.641 | 13.31 | 20.76 |
IB.67 | 0.232 | 8.84 | 38.10 |
IB.70 | 0.323 | 7.67 | 23.75 |
IB.88 | 0.300 | 4.09 | 13.63 |
布德松 | 0.101 | 0.68 | 6.73 |
丙酸氟替卡松 | 0.086 | 0.36 | 4.18 |
(e)大鼠中的肝糖原沉积
对称重190-220g的雄性Sprague Dawley大鼠进行双肾上腺切除,并在整个试验中保持在0.9%盐水溶液中。在肾上腺切除的第5天和第6天,将动物分成不同的组,将在冷盐水中制备的测试化合物(声波处理30min)气管内灌注2个剂量的3mg/kg,间隔24小时。在最后的处理之后15小时,杀死动物,切下肝并称重。 通过蒽酮方法测定肝的糖原含量。简言之,将所称量的肝组织用5%三氯乙酸匀浆,将上清液与乙醇混合并保持过夜进行沉淀。如此提取的糖原估计为在620nm下加入蒽酮试剂进行酸水解之后所产生的葡萄糖。糖原含量表示为mg/100g肝。
表11:大鼠中的肝糖原沉积
化合物编号 | 剂量(mg/kg) | 糖原含量 (mg/100g肝) | %胸腺抑制率 |
IA.3 | 3 | -13.6 | -2.42 |
IB.4 | 3 | -5.77 | -9.68 |
IB.50 | 3 | 6.67 | 5.48 |
IC.3 | 3 | -11.34 | -2.43 |
丙酸氟替卡松 | 3 | 1514.65 | 70.17 |
糠酸莫米松 | 3 | 1117.32 | 43.51 |
布德松 | 3 | 552.77 | 65.02 |
(f)通过静脉内施用途径的全身活性的评估
为评价静脉内施用的全身副作用,采用在雄性SD大鼠中的棉球肉芽肿试验(空白棉球)。将重20mg的灭菌棉球手术植入两侧的肩胛区。从植入的第二天开始,将溶解在Pharmasove(Pharmasolve 66.67%,在盐水中)或载体中的化合物连续三天以1.6mg/kg的剂量进行静脉内施用。在植入的第五天,取出球以及肉芽肿。同样将胸腺从各动物中分离并称重。将具有肉芽肿的球在60℃下干燥20小时并称重。将干肉芽肿和胸腺的平均重量以及体重增加/100g体重与载体对照组进行比较。
本发明式I的化合物通过静脉内施用不诱导任何显著的胸腺和体重增加抑制。此外,通过静脉内施用途径,不存在显著的棉球肉芽肿抑制,因此这清楚地表明缺乏全身活性,并且因此表明式I化合物优异的全身安全特性。
表12:静脉内施用途径的活性
化合物编号 | 剂量mcg(3 天),静脉内 | 肉芽肿的平均 抑制率(%) | 平均胸腺重量减少 (%)* |
IA.3 | 1600 | 3.98 | 6.37 |
IA.11 | 1600 | 16.65 | -17.88 |
IA.89 | 1600 | 15.90 | 6.54 |
IC.3 | 1600 | 12.09 | -10.38 |
IC.5 | 1600 | -22.20 | 1.67 |
IA.143 | 1600 | -3.01 | 5.51 |
丙酸氟替卡松 | 1600 | 55.62 | 75.71 |
*当与载体对照比较时,在所有化合物中体重增加在统计学上是不显著的。
结论
本发明式I的化合物在体外对糖皮质激素受体具有有效的结合。在体内模型中——其包括巴豆油诱导的耳水肿、棉球诱导的肉芽肿以及交联葡聚糖诱导的肺水肿筛选,本发明的化合物表现出显著的抗炎活性。在棉球肉芽肿中,由化合物导致的胸腺退化以及体重增加甚至在高达每球100-1000mcg的剂量水平下不存在或者是不显著的。类似的行为在交联葡聚糖诱导的肺水肿模型情况中又被观察到,即使在化合物以非常高的剂量给予时也是如此,这清楚地证明这些化合物在局部施用之后不引起任何不利的全身作用。全身副作用不存在或者不显著进一步通过测量气管内施用之后大鼠中的肝糖原沉积,以及通过测量静脉内施用后胸腺和体重增加的抑制得以证实。
因此,在本发明中描述的式I的化合物是有效的抗炎糖皮质激素,其甚至在显著高于治疗剂量的剂量下具有微小的或者没有显著的全身活性。由于无显著的全身作用,因此本发明的化合物具有抗炎活性对全身副作用的高治疗指数,这是利用糖皮质激素进行治疗所高度期望的。
Claims (7)
1.式I的化合物11β-羟基雄甾-4-烯-3-酮,及其生理学上可接受的盐:
式I
其中:
Z表示O或S;
R1表示氢或甲基,其可以处于α或β-构型;
R2和R3相同或不同,并且各自独立地表示氢、F或Cl;
R5表示选自(C2-C3)-烷基、(C4)-环烷基或未取代的杂环的基团;和
R4表示选自A、B和C的部分,条件是当R4表示部分(C)时,Z是S:
其中:
m1是1;
m2是0或1;
m3是0或1;
n1是0或1;
R6表示选自(C1)-烷基和苯基的基团,其中苯基是未取代的或者被一个或多个选自下述的取代基取代:(C1)-烷基、卤素、O-(C1)-烷基、S(O)0-2(C1)-烷基;
P、Q和L独立地是氢;
X表示双键或三键;和
J和K独立地选自:氢、(C1-C10)-烷基;
或者J和K与它们所连接的碳原子结合在一起,表示(C3-C13)-环烷基或-CO-基团;
或者当n1是0时,J、K和L不存在;
R7表示选自氢、卤素和苯基的基团,其中环或环体系是未取代的或者如上所述被取代;其中:
杂环是指未取代的3至5元环;并且除了碳之外,还含有杂原子,所述杂原子是氧或硫。
7.根据权利要求1所述的11β-羟基雄甾-4-烯-3-酮,选自:
S-[2-(4-氯苯基)-2-氧代乙基]6α,9α-二氟-11β-羟基-16α-甲基-3-氧代-17α-丙酰氧基雄甾-1,4-二烯-17β-硫代羟酸酯,
S-[2-(4-氟苯基)-2-氧代乙基]6α,9α-二氟-11β-羟基-16α-甲基-3-氧代-17α-丙酰氧基雄甾-1,4-二烯-17β-硫代羟酸酯,
S-[2-(2,4-二氟苯基)-2-氧代乙基]6α,9α-二氟-11β-羟基-16α-甲基-3-氧代-17α-丙酰氧基雄甾-1,4-二烯-17β-硫代羟酸酯,
S-[2-(2,4-二氯苯基)-2-氧代乙基]6α,9α-二氟-11β-羟基-16α-甲基-3-氧代-17α-丙酰氧基雄甾-1,4-二烯-17β-硫代羟酸酯,
S-[2-(3,4-二氯苯基)-2-氧代乙基]6α,9α-二氟-11β-羟基-16α-甲基-3-氧代-17α-丙酰氧基雄甾-1,4-二烯-17β-硫代羟酸酯,
S-[2-氧代丙基]6α,9α-二氟-11β-羟基-16α-甲基-3-氧代-17α-丙酰氧基雄甾-1,4-二烯-17β-硫代羟酸酯,
2-氧代丙基6α,9α-二氟-11β-羟基-16α-甲基-3-氧代-17α-丙酰氧基雄甾-1,4-二烯-17β-羧酸酯,
S-[2-氧代-2-(4-三氟甲氧苯基)乙基]6α,9α-二氟-11β-羟基-16α-甲基-3-氧代-17α-丙酰氧基雄甾-1,4-二烯-17β-硫代羟酸酯,
S-[2-氧代-2-(4-三氟甲基苯基)乙基]6α,9α-二氟-11β-羟基-16α-甲基-3-氧代-17α-丙酰氧基雄甾-1,4-二烯-17β-硫代羟酸酯,
2-(4-甲磺酰苯基)-2-氧代乙基6α,9α-二氟-11β-羟基-16α-甲基-3-氧代-17α-丙酰氧基雄甾-1,4-二烯-17β-羧酸酯,
S-[2-(4-甲磺酰苯基)-2-氧代乙基]6α,9α-二氟-11β-羟基-16α-甲基-3-氧代-17α-丙酰氧基雄甾-1,4-二烯-17β-硫代羟酸酯,
2-氧代-2-苯乙基6α,9α-二氟-11β-羟基-16α-甲基-3-氧代-17α-丙酰氧基雄甾-1,4-二烯-17β-羧酸酯,
S-[2-氧代-2-苯乙基]6α,9α-二氟-11β-羟基-16α-甲基-3-氧代-17α-丙酰氧基雄甾-1,4-二烯-17β-硫代羟酸酯,
S-[2-氧代-2-(2,4,6-三甲基苯基)乙基]6α,9α-二氟-11β-羟基-16α-甲基-3-氧代-17α-丙酰氧基雄甾-1,4-二烯-17β-硫代羟酸酯,
S-[1,1-二甲基-2-氧代-2-苯乙基]6α,9α-二氟-11β-羟基-16α-甲基-3-氧代-17α-丙酰氧基雄甾-1,4-二烯-17β-硫代羟酸酯,
S-[2-(4-甲氧苯基)-2-氧代乙基]6α,9α-二氟-11β-羟基-16α-甲基-17α-(2-甲基丙酰氧基)-3-氧代雄甾-1,4-二烯-17β-硫代羟酸酯,
S-[2-氧代-2-(4-三氟甲基苯基)乙基]17α-环丁基羰氧基-6α,9α-二氟-11β-羟基-16α-甲基-3--氧代雄甾-1,4-二烯-17β-硫代羟酸酯,
S-[2-(2,4-二氟苯基)-2-氧代乙基]17α-环丁基羰氧基-6α,9α-二氟-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-硫代羟酸酯,
S-[2-(4-甲氧苯基)-2-氧代乙基]17α-环丁基羰氧基-6α,9α-二氟-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-硫代羟酸酯,
S-[2-(2,4-二氟苯基)-2-氧代乙基]9α-氟-17α-[(2-呋喃甲酰基)氧]-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-硫代羟酸酯,
S-[2-(4-氯苯基)-2-氧代乙基]9α-氟-17α-[(2-呋喃甲酰基)氧]-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-硫代羟酸酯,
S-[2-(4-甲氧苯基)-2-氧代乙基]9α-氟-17α-[(2-呋喃甲酰基)氧]-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-硫代羟酸酯,
S-[2-(4-氟苯基)-2-氧代乙基]9α-氟-17α-[(2-呋喃甲酰基)氧]-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-硫代羟酸酯,
S-[2-(4-氯苯基)-2-氧代乙基]6α,9α-二氟-17α-[(2-呋喃甲酰基)氧]-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-硫代羟酸酯,
S-[2-(3,4-二甲基苯基)-2-氧代乙基]6α,9α-二氟-11β-羟基-16α-甲基-3-氧代-17α-丙酰氧基雄甾-1,4-二烯-17β-硫代羟酸酯,
S-[2-(3-氯苯基)-2-氧代乙基]6α,9α-二氟-17α-[(2-呋喃甲酰基)氧]-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-硫代羟酸酯,
S-(4-羟基-丁-2-炔基)6α,9α-二氟-17α-[(2-呋喃甲酰基)氧]-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-硫代羟酸酯,
S-(4-正丙基羰氧基-丁-2-炔基)6α,9α-二氟-11β-羟基-16α-甲基-3-氧代-17α-丙酰氧基雄甾-1,4-二烯-17β-硫代羟酸酯,
S-[4-(乙氧基-1,2-二氧代乙基-(E)-丁-2-烯基]6α,9α-二氟-11β-羟基-16α-甲基-3-氧代-17α-丙酰氧基雄甾-1,4-二烯-17β-硫代羟酸酯,
S-[4-(2-乙氧基-1,2-二氧代乙基)氧-(E)-丁-2-烯基]6α,9α-二氟-17α-[(2-呋喃甲酰基)氧]-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-硫代羟酸酯,
S-[4-正丙基羰氧基-丁-2-炔基]6α,9α-二氟-17α-[(2-呋喃甲酰基)氧]-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-硫代羟酸酯,
S-[4-(2-甲基丙酰氧基)-丁-2-炔基]6α,9α-二氟-17α-[(2-呋喃甲酰基)氧]-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-硫代羟酸酯,
S-[4-(2,2-二甲基丙酰氧基)-丁-2-炔基]6α,9α-二氟-17α-[(2-呋喃甲酰基)氧]-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-硫代羟酸酯,
S-[4-(2,2-二甲基丙酰氧基)-丁-2-炔基]6α,9α二氟-11β-羟基-16α-甲基-3-氧代-17α-丙酰氧基雄甾-1,4-二烯-17β-硫代羟酸酯,
S-[4-正丙基羰氧基-(Z)-丁-2-烯基]6α,9α-二氟-17α-[(2-呋喃甲酰基)氧]-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-硫代羟酸酯,
S-[4-(2-乙氧基-1,2-二氧代乙基)氧-丁-2-炔基]6α,9α-二氟-17α-[(2-呋喃甲酰基)氧]-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-硫代羟酸酯,
S-[4-正丙基羰氧基-丁-2-炔基]6α,9α-二氟-11β-羟基-16α-甲基-3-氧代-17α-[(2-噻吩甲酰基)氧]雄甾-1,4-二烯-17β-硫代羟酸酯,
S-[(4-环丙基羰氧基)-丁-2-炔基]6α,9α-二氟-17α-[(2-呋喃甲酰基)氧]-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-硫代羟酸酯,
S-[(4-乙氧基羰氧基)-丁-2-炔基]6α,9α二氟-17α-[(2-呋喃甲酰基)氧]-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-硫代羟酸酯,
S-[4-(2-甲基丙氧基羰氧基)-丁-2-炔基]6α,9α-二氟-17α-[(2-呋喃甲酰基)氧]-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-硫代羟酸酯,
S-[4-(3-氯丙基羰氧基)-丁-2-炔基]6α,9α-二氟-17α-[(2-呋喃甲酰基)氧]-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-硫代羟酸酯,
S-[4-二氯乙酰氧基-丁-2-炔基]6α,9α-氟-17α-[(2-呋喃甲酰基)氧]-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-硫代羟酸酯,
S-(4-丙酰氧基-丁-2-炔基)6α,9α-二氟-17α-[(2-呋喃甲酰基)氧]-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-硫代羟酸酯,
S-[4-(3,3,3-三氟丙酰氧基)-丁-2-炔基]6α,9α-二氟-17α-[(2-呋喃甲酰基)氧]-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-硫代羟酸酯,
S-[4-(乙氧基乙酰氧基)-丁-2-炔基]6α,9α-二氟-17α-[(2-呋喃甲酰基)氧]-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-硫代羟酸酯,
S-(4-乙酰氧基-丁-2-炔基)6α,9α-二氟-17α-[(2-呋喃甲酰基)氧]-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-硫代羟酸酯,
S-[4-(4-乙氧基丁基-1,4-二酮)氧-丁-2-炔基]6α,9α-二氟-17α-[(2-呋喃甲酰基)氧]-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-硫代羟酸酯,
S-[4-(4-甲氧基丁基-1,4-二酮)氧-丁-2-炔基]6α,9α-二氟-17α-[(2-呋喃甲酰)-氧]-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-硫代羟酸酯,
S-[4-(3-氯-2,2-二甲基丙酰氧基)-丁-2-炔基]6α,9α-二氟-17α-[(2-呋喃甲酰基)氧]-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-硫代羟酸酯,
S-[4-(4-甲氧基-(E)-丁-2-烯-1,4-二酮)氧-丁-2-炔基]6α,9α-二氟-17α-[(2-呋喃甲酰基)氧]-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-硫代羟酸酯,
S-[4-(3-甲基-1-氧代丁氧基)-丁-2-炔基]6α,9α-二氟-17α-[(2-呋喃甲酰基)氧]-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-硫代羟酸酯,
S-[4-(2-乙基-1-氧代丁氧基)-丁-2-炔基]6α,9α-二氟-17α-[(2-呋喃甲酰基)氧]-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-硫代羟酸酯,
S-[4-(N,N-二甲氨基羰氧基)-丁-2-炔基]6α,9α-二氟-17α-[(2-呋喃甲酰基)氧]-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-硫代羟酸酯,
S-[4-(2-氯-2-甲基丙酰氧基)-丁-2-炔基]6α,9α-二氟-17α-[(2-呋喃甲酰基)氧]-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-硫代羟酸酯,
S-[4-(4-甲基-1-氧代戊氧基)-丁-2-炔基]6α,9α-二氟-17α-[(2-呋喃甲酰基)氧]-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-硫代羟酸酯,
S-[4-(4-甲氧基-(Z)-丁-2-烯-1,4-二酮)氧-丁-2-炔基]6α,9α-二氟-17α-[(2-呋喃甲酰基)氧]-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-硫代羟酸酯,
S-[4-(R)-2,2-二甲基-1,3-二氧戊环-4-基-甲氧基羰氧基)-丁-2-炔基]6α,9α-二氟-17α-[(2-呋喃甲酰基)氧]-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-硫代羟酸酯,
S-(4-乙氧基-丁-2-炔基)6α,9α-二氟-17α-[(2-呋喃甲酰基)氧]-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-硫代羟酸酯,
6α,9α-二氟-11β-羟基-16α-甲基-3-氧代-17α-丙酰氧基雄甾-1,4-二烯-17β-羰基次磺酸氟甲酯,
6α,9α-二氟-17α-[(2-呋喃甲酰基)氧]-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-羰基次磺酸氟甲酯,
6α,9α-二氟-17α-[(2-呋喃甲酰基)氧]-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-羰基次磺酸(4-氟苯基)甲酯,
6α,9α-二氟-17α-[(2-呋喃甲酰基)氧]-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-羰基次磺酸(4-三氟甲基苯基)甲酯,
6α,9α-二氟-17α-[(2-呋喃甲酰基)氧]-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-羰基次磺酸(4-氯苯基)甲酯,
6α,9α-二氟-11β-羟基-16α-甲基-3-氧代-17α-丙酰氧基雄甾-1,4-二烯-17β-羰基次磺酸(4-三氟甲基苯基)甲酯,
9α-氟-17α-[(2-呋喃甲酰基)氧]-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-羰基次磺酸(4-氟苯基)甲酯,
6α,9α-二氟-11β-羟基-16α-甲基-3-氧代-17α-丙酰氧基雄甾-1,4-二烯-17β-羰基次磺酸甲酯,
6α,9α二氟-17α-[(2-呋喃甲酰基)氧]-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-羰基次磺酸甲酯,
S-[4-(4-甲基-1-氧代戊氧基)-丁-2-炔基]6α,9α-二氟-17α-[(2-呋喃甲酰基)氧]-11β-羟基-16α-甲基-3-氧代雄甾-1,4-二烯-17β-硫代羟酸酯。
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PCT/IN2007/000039 WO2007099548A2 (en) | 2006-01-27 | 2007-01-29 | Novel 11 beta - hydroxyandrosta-4-ene-3-ones |
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TWI374147B (en) | 2006-01-27 | 2012-10-11 | Sun Pharma Advance Res Company Ltd | Novel 11β-hydroxyandrosta-4-ene-3-ones |
AU2013202835B2 (en) * | 2006-06-14 | 2015-11-12 | Generics [Uk] Limited | Process for the preparation of S-fluoromethyl-6,9-difluoro-11-hydroxy-16-methyl-17-propionyloxy-3-oxo-androsta-1, 4-diene-17-carbothioate and intermediates |
CA2654644C (en) * | 2006-06-14 | 2014-02-18 | Generics [Uk] Limited | Novel process and intermediates |
JP2012528140A (ja) | 2009-05-29 | 2012-11-12 | ファイザー・リミテッド | 新規なグルココルチコイド受容体アゴニスト |
EP2560634A1 (en) | 2010-04-23 | 2013-02-27 | Piramal Enterprises Limited | Nitric oxide releasing prodrugs of therapeutic agents |
KR101103943B1 (ko) * | 2011-12-12 | 2012-01-12 | 오수련 | 무료이용쿠폰을 활용한 제휴사 및 리셀러의 온라인 제휴마케팅 운영방법 |
WO2013133980A1 (en) * | 2012-03-05 | 2013-09-12 | Bausch & Lomb Incorporated | Nitroxy derivatives of soft steroids |
CA2897571C (en) | 2013-01-21 | 2018-12-18 | Apparao Satyam | Nitric oxide releasing prodrugs of therapeutic agents containing at least one carboxylic acid group |
CA2912400A1 (en) * | 2013-05-28 | 2014-12-04 | Sun Pharma Advanced Research Company Limited | Methods for treatment of inflammatory conditions using s-[4-(3-fluoro-3-methylbutyryloxy)but-2-ynyl]6.alpha.,9.alpha.-difluoro-17.alpha.-(furan-2-yl)carbonyloxy-11.beta.-hydroxy-16.alpha.-methyl-3-oxoandrosta-1,4-diene-17.beta.-carbothioate |
CN106279341A (zh) * | 2015-05-11 | 2017-01-04 | 正大天晴药业集团股份有限公司 | 一种糠酸氟替卡松的制备方法 |
CN109438543B (zh) * | 2018-11-28 | 2020-09-15 | 广州健康元呼吸药物工程技术有限公司 | 一种高纯度糠酸氟替卡松的制备方法 |
CN111662353A (zh) * | 2019-03-05 | 2020-09-15 | 上海谷森医药有限公司 | 一种糠酸氟替卡松晶型1的制备方法 |
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US3007923A (en) | 1959-01-22 | 1961-11-07 | Lab Francais Chimiotherapie | Process for the fluorination of 9beta, 11beta-epoxy and 5alpha, 6alpha-epoxy steroids |
SE378109B (zh) | 1972-05-19 | 1975-08-18 | Bofors Ab | |
US4188385A (en) * | 1978-04-05 | 1980-02-12 | Syntex (U.S.A.) Inc. | Thioetianic acid derivatives |
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US6610675B1 (en) * | 1980-07-10 | 2003-08-26 | Nicholas S. Bodor | Inactive metabolite approach to soft drug design |
US4996335A (en) * | 1980-07-10 | 1991-02-26 | Nicholas S. Bodor | Soft steroids having anti-inflammatory activity |
SE449106B (sv) * | 1980-07-10 | 1987-04-06 | Otsuka Pharma Co Ltd | Steroid med anti-inflammatorisk verkan samt komposition innehallande denna |
ZA814440B (en) * | 1980-07-10 | 1982-10-27 | Otsuka Pharma Co Ltd | Soft steroids having anti-inflammatory activity |
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US5981517A (en) * | 1996-05-09 | 1999-11-09 | Soft Drugs, Inc. | Androstene derivatives |
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